SK285908B6 - Aminocyclohexyl ether compound, composition comprising it and use thereof in the manufacture of medicaments and in the treatment of diseases - Google Patents

Abstract

Disclosed are antiarrhytmic aminocyclohexyl ether compounds of formula (XV), their use in the manufacture of medicaments and pharmaceutical compositions comprising them.

Description

The present invention relates to aminocyclohexyl ether compounds, pharmaceutical compositions and complexes containing them, and their therapeutic use.

BACKGROUND OF THE INVENTION

Arrhythmia is a departure from the normal rhythm of the heart beat and is generally the end result of a change in the structure, number, or function of the ion channels. Ventricular and atrial arrhythmias are known. The main cause of cardiac arrhythmia death is a type of ventricular arrhythmia known as ventricular fibrillation (VF). Conservative estimates indicate that in the US alone, more than one million patients each have a coronary event (defined as a myocardial infarction or fatal coronary heart disease) each year. Of these, 650000 are the first cardiac event and 450000 are the recurrent event. About one third of people die of the incident. Over 250,000 people die annually of a heart attack within 1 hour of the onset of symptoms and before they reach the hospital. These are sudden deaths due to cardiac arrest usually after ventricular fibrillation.

Atrial fibrillation (AF) is the most common arrhythmia observed in clinical practice and is the cause of death for many people (Pritchett EL, M. Engl. J. Med. 327 (14): 1031, October 1, 1992. discussion 1031-2) Kannel and Wolf, Am Heart J. 123 (1): 264-7, January 1992). Atrial fibrillation increases with aging populations and it is estimated that 3-5% of patients over 60 years have AF (Karinl WB, Abbot RD, Savage D, D., McNamara PM, M. Engl. Med. 306 (17): 1018-). 22, 1982, Wolf PA, Abbot RD, Kannel WB, Stroke, 22 (8): 983-8, 1991). Although atrial fibrillation is rarely fatal, it can damage heart function and is a major cause of heart attack (Hinton RC, Kistler JP, Fallon JT, Friedlich A, L, Fisher CM., American Joumal of Cardiology 40 (4): 509 - 13 1977: Wolf PA, Abbot RD, Kannel WB, Archives of Inlemal Medicine (147 (9): 1561-4, 1987; Wolf PA, Abboz RD, Kannet WB Stroke. 22 (8): 983-8, 1991: Cabin HS, Clubb KS, Hall C, Perlmutter R-A, Fienstein AR, American Joumal of Cardiology 65 (16): 1112-6, 1990).

Antiarrhythmic agents have been developed to prevent and alleviate cardiac arrhythmias. For example, class I antiarrhythmic compounds have been used to treat supraventricular arrhythmias and ventricular arrhythmias. The treatment of ventricular arrhythmia is very important as this arrhythmia may be fatal. Serious ventricular arrhythmias (tachycardia ventricular and fibrillation ventricular) are most common in ischemia and / or myocardial infarction. Ventricular fibrillation often occurs at the onset of acute myocardial ischemia before a heart attack develops. There is currently no effective pharmacotherapy for the treatment and / or prevention of ventricular fibrillation during acute ischemia. In addition, many class 1 antiarrhythmic compounds may actually increase mortality in patients who have already had a myocardial infarction.

Class Ia, 1c and III antiarrhythmic drugs have been used to convert the initial AF attack to sinus rhythm and prevent recurrence of arrhythmias (Fuch and Podrid, 1992; Nattel S, Hadjis T, Talajic M, Drugs 48 (3): 345-71 , 1994). However, pharmacotherapy is often limited by contradictory effects, including the possibility of increasing mortality and inadequate efficacy (Feld G1K., Circulation 83 (6): 2248-50, 1990; Copien SE, Antman EM, Berlin JA., Hewitt P., Chalmers T. C. Circulation 1991: 83 (2): 714 and Circulation

82 (4): 1106-16, 1990: Fiaker G. C., Blackshear J. L., McBrid R., Kronmal R. A., Halperin J. L., Hart R. G., Journal of the American College of Cardiogology 20 (3): 527-32, 1992; CAST, N. Engl. J. Med. 321: 406 (1989); Nattel S., Cardiovascular Research 37 (3): 567-77 (1998). The degree of conversion for class I antiarrhythmic drugs is 50-90% (Nattel S., Hadjis T., Talajic M., Drugs 48 (3): 345-71, 1994: Steinbeck G., Remp T., Hoffmann E., Journal of Cardiovascular Electrophysiology 9 (8 Suppl): 104-8, 1998). Class III antiarrhythmic agents are more effective at atrial shake ending than for AF and generally less effective than class I drugs for ending AF (Nattel S., Hadjis T., Talajic M., Drugs 48 (3): 345-71, 1994: Capucci A , Aschieri D., Villani GQ, Drugs & Aging 13 (1): 51-70, 1998). Examples of such drugs include ibutilide, dofetilide and sotalol. The degree of conversion for these drugs is 30-50% for the onset of AF (Capuchia A., Aschieri D., Villani GQ, Drugs & Aging 13 (1): 51-70, 1998) and also associated with the risk of inducing "Torsades de Pointes' ventricular tachyarrhythmia. For ibutilide, the risk of ventricular proarrhythmia is estimated to be 4.4% and 1.7% in patients requiring cardioversion for sustained ventricular arrhythmias (Kowey PR, VanderLugt JT, Luderer JR, American Journal of Cardiology 78 (8A): 46-52, 1996) ). These cases are extremely tragic because AF itself is rarely fatal.

Therefore, there is a need for a new method of antiarrhythmic treatment of both ventricular arrhythmia and arterial arrhythmia. The present invention satisfies this need and further provides other associated advantages.

SUMMARY OF THE INVENTION

The present invention provides an aminocyclohexyl ether compound of formula (XV) or a solvate thereof, or a pharmaceutically acceptable salt thereof:

where, independently for each occurrence,

R 1 and R ₂ , taken together with the nitrogen atom to which they are directly attached in formula (XV), form a ring represented by formula (II):

(II), wherein the ring of formula (II) is formed by a nitrogen atom and at the same time by three to nine other ring atoms independently selected from carbon, nitrogen, oxygen and sulfur; wherein any two adjacent ring atoms may be linked to each other by a single or double bond, and any one or more additional ring carbon atoms may be substituted by one or two substituents selected from hydrogen, hydroxy, C 1 -C ₃ hydroxyalkyl, oxo, C _{2 C4} acyl, C _r CjaIkylovej group, C ₂ -C ₄ alkylcarboxy, C | -C ₃ alkoxy, C | -C ₂₀ -alkanoyl-oxy, or may be substituted to form a spiro five- or six-membered heterocyclic ring containing one or two heteroatoms selected from oxygen and sulfur; and any two are seated more ring carbon atoms may be fused to the C ₃ -C _{g of} a carbocyclic ring, and any one or more additional ring nitrogen is substituted with substituents selected from hydrogen, C -C alkyl, C ₂ -C ₄ acyl, C ₂ -C ₄ hydroxyalkyl and _C-C8 alkoxyalkyl; or R 1 and R ₂ , taken together with the nitrogen atom to which they are directly attached in formula (XV), may then form a bicyclic ring system selected from 3-azabicyclo [3.2.2] nonan-3-yl, 2-azabicyclo [2.2.2] octan-2-yl, 3-azabicyclo [3.1.0] hexan-3-yl, and 3-azabicyclo [3.2.0] heptan-3-yl;

A is selected from any of formulas (III), (IV), (V) and (VI):

wherein R _7, R _{1 O,} R i R ₁₂ are hydrogen, R ₈ and R ₉ are independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine, methanesulphonamido, metanoyloxyskupiny, methoxycarbonyl, nitro, sulfamyl groups , thiomethyl, trifluoromethyl, methyl, ethyl, methoxy, ethoxy and _NH2, provided that at least one of _Rg and _R9 is not hydrogen; and Z is selected from oxygen and sulfur;

including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures.

Preferred is a compound selected from the group consisting of: (+) - trans - [2- (4-morpholinyl) -1- (2-naphthenethoxy)] cyclohexane; (-) - trans- [2- (4-morpholinyl) -l- (2-naphthenethoxy)] cyclohexane; (+) - trans - [2- (4-fluoropholinyl) -1- (naphthenethoxy) cyclohexane; (-) - tra / N- [2- (4-morpholinyl) -l- (l-naphthenethoxy)] cyclohexane; (+) - / trans- [2- (4-morpholinyl) -l- (4-bromophenethoxy)] cyclohexane;

(-) - / raíi5- [2- (4-morpholinyl) -l- (4-bromophenethoxy)] cyclohexane;

(+) - / r 'bis- [2- (4-morpholinyl) -l- (3,4-dimetoxyfenetoxy)] cyclohexane;

(-) - trans - [2- (4-Morpholinyl) -1- (3,4-dimethoxyphenethoxy)] cyclohexane;

(+) - trans - [2- (1-pyrrolidinyl) -1- (1-naphthethoxy)] cyclohexane;

(-) - trans - [2- (1-Pyrrolidinyl) -1- (1-naphlenethoxy)] cyclohexane; (+) - trans - [2- (4-Morpholinyl) -1- (2- (benzo [b] thiophen-3-yl) ethoxy)] cyclohexane;

(-) - / rQn.?-[2-(4-morfolinyl)-l-(2-(benzo[b]tiofen-3-yl)ctoxy)]cyklohcxánu;

(+) - trans - [2- (4-Morpholinyl) -1- (2- (benzo [b] thiophen-4-yl) ethoxy)] cyclohexane;

(-L / r ».s' [2-r4-morpholin [) - I- (2- (benzo [b] thiophen-4-yl) ethoxy)] cyclohexane;

(+) - íranx- [2- (4-morpholinyl) -l- (3-bromophenethoxy)] cyclohexane;

(-) - trans - [2- (4-Morpholinyl) -1- (3-bromophenethoxy)] cyclohexane;

(+) - Zra 'of 5- (2- (4-morpholinyl) -l- (2-bromophenethoxy)] cyclohexane;

(-) - trans - [2- (4-Morpholinyl) -1- (2-bromophenethoxy)] cyclohexane;

(1R, 2R) / (1S, 2S) -2- (4-Morpholinyl) -1- (3,4-dichlorophenethoxy) cyclohexane;

(R, 2 R) / (S, 2S) -2- (3-ketopyrrolidinyl) -l- (l-naphthenethoxy) cyclohexane;

(1R, 2R) / (1S, 2S) -2- (1-Acetylpiperazinyl) -1- (2-naphthenethoxy) cyclohexane;

(1R, 2R) / (1S, 2S) -2- (3-ketopyrrolidinyl) -1- (2,6-dichlorophenethoxy) cyclohexane;

(1R, 2R) / (1S, 2S) -2- [1,4-dioxa-7-azaspiro [4.4] non-7-yl] -1- (1-naphthenethoxy) cyclohexane;

(1R, 2S) / (1S, 2R) -2- (4-Morpholinyl) -1 - [(2-trifluoromethyl) phenethoxy] cyclohexane;

(1R, 2R) / (1S, 2S) -2- (3-acetoxypyrrolidinyl) -1- (1-naphthethoxy) cyclohexane;

(1R, 2R) / (1S, 2S) -2- (3-Hydroxy-pyrrolidinyl) -1- (2,6-dichloro-ethoxy) -cyclohexane;

(1R, 2R) / (1S, 2S) -2- (3-thiolidinyl) -1- (2,6-dichlorophenethoxy) cyclohexane; and (1R, 2S) / (1S, 2R) -2- (3-ketopyrrolidinyl) -1- (1-naphthethoxy) cyclohexane;

and pharmaceutically acceptable salts thereof, including mixtures thereof.

The present invention also provides a composition comprising a compound of formula (XV) in combination with a pharmaceutically acceptable carrier, excipient or diluent.

The invention further provides the use of a compound of formula (XV) in the manufacture of a medicament.

The present invention also provides a compound of formula (XV) or a composition comprising the compound for use in treating or preventing arrhythmia of a warm-blooded animal;

for use in modulating the activity of ion channels of a warm-blooded animal;

for use in modulating ion channel activity in vitro;

for use in the treatment or prevention of a central nervous system disease of a warm-blooded animal;

for use in treating or preventing convulsions of a warm-blooded animal;

for use in treating or preventing epileptic convulsions of a warm-blooded animal;

for use in treating or preventing depression, anxiety or schizophrenia of a warm-blooded animal;

for use in treating or preventing Parkinson's disease in a warm-blooded animal;

for use in the treatment or prevention of a warm-blooded animal respiratory disease;

for use in treating or preventing cystic fibrosis of a warm-blooded animal;

for use in treating or preventing asthma of a warm-blooded animal;

for use in treating or preventing a cough of a warm-blooded animal;

for use in treating or preventing inflammation of a warm-blooded animal;

for use in treating or preventing arthritis of a warm-blooded animal;

for use in treating or preventing a warm-blooded animal allergy;

for use in treating or preventing gastrointestinal diseases of a warm-blooded animal;

for use in treating or preventing urine incontinence in a warm-blooded animal;

for use in treating or preventing the irritation syndrome of the colon of a warm-blooded animal;

for use in treating or preventing cardiovascular diseases in a warm-blooded animal;

for use in treating or preventing cerebral or cardiac ischemia of a warm-blooded animal;

for use in treating or preventing hypertension in a warm-blooded animal;

for use in treating or preventing long-QT syndrome of a warm-blooded animal;

for use in treating or preventing stroke of a warm-blooded animal;

for use in treating or preventing migraine of a warm-blooded animal;

for use in treating or preventing ocular diseases of a warm-blooded animal;

for use in treating or preventing diabetes mellitus of a warm-blooded animal;

for use in treating or preventing a warm-blooded animal myopathy;

for use in treating or preventing Becker myotonia in a warm-blooded animal;

for use in treating or preventing myasthenia gravis of a warm-blooded animal;

for use in treating or preventing paramyotonia congentia warm-blooded animal;

for use in treating or preventing malignant hyperthermia of a warm-blooded animal;

for use in treating or preventing hyperkalemic periodic paralysis of a warm-blooded animal;

for use in treating or preventing Thomsen's myotonia in a warm-blooded animal;

for use in treating or preventing autoimmune diseases of a warm-blooded animal;

for use in treating or preventing graft rejection in an organ transplant or a bone marrow transplant of a warm-blooded animal;

for use in producing local analgesia or anesthesia of a warm-blooded animal;

for use in treating or preventing heart failure of a warm-blooded animal;

for use in treating or preventing hypotension of a warm-blooded animal;

for use in treating or preventing Alzheimer's disease in a warm-blooded animal;

for use in treating or preventing dementia of a warm-blooded animal;

for use in treating or preventing alopecia of a warm-blooded animal;

for use in increasing the libido of a warm-blooded animal; for use in treating or preventing atrial arrhythmia of a warm-blooded animal;

for use in treating or preventing ventricular arrhythmias in a warm-blooded animal;

for use in treating or preventing atria of a warm-blooded atrium and for use in treating or preventing atrial fibrillation of a warm-blooded animal.

If, according to the invention, an asymmetric divalent radical is present, then the divalent radical may be positioned in any manner that provides a stable chemical structure. For example, for compounds containing the group AX-CH (R ₅ ) -, wherein X is C (R ₁₄ , R ₆ ) -Y, the invention includes compounds containing such groups

AC (R ₁₄ , R ₆ ) -Y-CH (R ₅ ) - as well as AYC (R ₁₄ , R ()) - CH (R ₅ ) - groups.

A wavy bond from the substituent to the center of the cyclohexane ring indicates that this group may be located on either side of the plane of the central ring.

The compounds of the present invention contain at least two asymmetric carbon atoms and may therefore exist in the form of enantiomers or diastereoisomers. Unless otherwise indicated, the present invention includes all enantiomeric and diastereoisomeric forms of the aminocyclohexyl ether compounds of the present invention. The invention also includes pure stereoisomers, mixtures of enantiomers and / or diastereoisomers, and mixtures of various compounds of the invention. Thus, the compounds of the present invention may exist in the form of racemates, racemic mixtures and individual diastereoisomers or enantiomers, the present invention encompassing all isomeric forms. The racemate or racemic mixture does not necessarily include a 50:50 mixture of stereoisomers.

This and other embodiments of the present invention will become apparent with reference to the following figures and detailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

Fig. 1 illustrates the reaction sequence further described in Example 1 for the preparation of the aminocyclohexyl ether compound of the present invention.

Fig. 2 illustrates a process by which either cis- or trans-aminocyclohexyl ether compounds of the present invention can be prepared.

Fig. 3 illustrates a synthetic approach by which either cis- or trans-steroisomeric compounds of the present invention can be prepared.

Fig. 4A and 4B illustrate the synthetic approach described in Example 15.

Overview of methods for preparing compounds of the present invention

The aminocyclohexyl ether compounds of the present invention contain amine and ether side chains at the 1,2-cyclohexane ring position. Therefore, these amine and ether side chains may be either cis or trans with respect to the plane of the cyclohexane ring. The present invention provides a synthetic methodology that allows the preparation of cis or trans compounds.

Trans compounds of the present invention can be prepared by analogous procedures to known synthetic methods (see, e.g., Shanklin Jr. et al., U.S. Patent 5,130,309). Figure 1 shows the preparation of the trans compounds of the present invention, which is described in detail in Example 1. As described in Figure 1, the preparation of the trans compounds can be carried out by the following four steps.

In the first step indicated by "i)" in the figure, the cyclohexane epoxide is subject to ring opening by an amine. See, for example, Szmuszkovicz, U.S. Pat. Patent 4,145,435. The reaction may be run at room temperature, but elevated temperature is typically preferred to complete the reaction at a commercially acceptable time. The reaction is typically carried out in a solvent such as water, the boiling point of the solvent being sufficient for the reaction. Equimolar amounts of amine and cyclohexene epoxide typically provide satisfactory results. In each case, the amine nitrogen reacts with the epoxy group to form 1-hydroxy-2-aminocyclohexane, the hydroxyl and amine groups typically being in a trans position. Various amine compounds and substituted cyclohexene oxides can undergo this general reaction. Figure 1 shows this reaction when the amine is morpholine and the cyclohexene oxide is unsubstituted.

In the case of other amines or substituted cyclohexene epoxides, which may contain other reactive groups, suitable protecting groups are introduced before step i). Suitable protecting groups are disclosed, for example, in Greene, " Protective Groups in Organic Chemistry ", John Wiley & Sons, New York, NY (1991).

In the second step indicated by the symbol "ii)" in Figure 1, the hydroxyl group formed from the epoxide is converted to the activated form. "Activated form" means that the hydroxyl group is converted to an easily leaving group. The leaving group exemplified in Figure 1 is a mesylate group, which is a preferred leaving group. However, the hydroxyl group can also be converted to other leaving groups which are well known in the art. In a typical reaction, the aminocyclohexanol compound is reacted with methanesulfonyl chloride in the presence of a base such as triethylamine (as shown in Figure 1). The reaction is successfully carried out at a temperature of about 0 ° C. In order to maximize the conversion of the more valuable aminocyclohexanol to the activated form, an excess of methanesulfonyl chloride (relative to aminocyclohexanol) is typically used. For some other aminocyclohexanols, it may be necessary to introduce suitable protecting groups before step ii). Suitable protecting groups are disclosed, for example, in Greene, " Protective Groups in Organic Chemistry ", John Wiley & Sons, New York, NY (1991).

In the third step, indicated by "iii)" in Figure 1, the alcohol is reacted with a strong base to give the alkoxide salt. The conversion of an alcohol to an alkoxide (also referred to as an alcoholate) using a strong base is a general reaction and occurs with many hydroxyl-containing compounds. In some cases, the alcohol may contain other reactive groups which it is desirable to protect from contacting the alcohol with a strong base. Suitable protecting groups are disclosed, for example, in Greene, " Protective Groups in Organic Chemistry ", John Wiley & Sons, New York, NY (1991). The alcohols are either commercially available or can be obtained by methods described in the literature or by methods derived therefrom, and these suitable procedures can be found in Chemical Abstracts and their registries published by the American Chemical Society.

In the fourth step indicated by the symbol "iv)" in the figure, the alcoholate of step "iii)" is reacted with the activated aminocyclohexanol of step "ii)". Generally speaking, a compound of the present invention can be prepared by reacting an activated form of a suitable 1,2-amino-cyclohexanol (1 mol) with an alcoholate (1.25 mol) prepared by reacting a selected alcohol (1.25 mol) with, for example, sodium hydride (1, 2). 3 mol). 1,2-Aminocyclohexanol (1 mol) can be activated by forming the appropriate mesylate from methanesulfonyl chloride (1.25 mol) and triethylamine (1.5 mol). The mesylate is quickly added to the alcoholate in a suitable solvent such as dimethylformamide. The reaction temperature is carefully monitored to eliminate an undesired side reaction, such as β-elimination. Generally, a temperature of 80-90 ° C for 2 hours is suitable for compound formation. Upon reaction, the desired product is isolated from the reaction mixture by conventional organic chemistry techniques and purified generally by column chromatography followed by recrystallization. In the appropriate step of the reaction sequence, it is possible to remove protecting groups. Suitable procedures are disclosed, for example, in Greene, "Protective Groups in Organic Chemistry", John Wiley & Sons, New York, NY (1991).

The reaction sequence described (shown in Figure 1) generates aminocyclohexyl ether as the free base. Pure enantiomers can be obtained by preparative chiral HPLC. The free base can be converted, if desired, to the monohydrochloride by known techniques and subsequently (if desired) to other acid addition salts by reaction with inorganic or organic salts. Acid addition salts can also be prepared by reacting the acid addition salt with an acid that is stronger than the anionic acid of the parent salt.

The cis or trans compounds of the present invention can be prepared by the procedure of Figure 2. As shown in Figure 2, 1,2-aminocyclohexanones can be prepared by Swem oxidation of the appropriate trans-1,2-aminocyclohexanol (which can be prepared as indicated). using a mixture of oxalyl chloride and dimethylsulfoxide (see, for example, Synthesis 1980, 165). Subsequent reduction of the aminocyclohexanone with lithium aluminum hydride or sodium borohydride affords a mixture of cis and trans aminocyclohexanol. The mixture of amino alcohols may be esterified with a suitable carboxylic acid by azeotropic distillation in toluene in the presence of a catalytic amount of p-toluenesulfonic acid to give a diasteroisomeric mixture of cis and trans esters. The mixture of diastereoisomeric esters can be separated by a person skilled in the art by preparative chromatography. The racemic cis or trans ester may then be reduced with sodium borohydride in the presence of Lewis acid to the corresponding racemic cis or trans ether (see, for example, J. Org. Chem. 25, 875, 1960 and Tetrahedron 18, 953, 1962). Racemic cis-ether can be resolved by preparative chiral HPLC as indicated for the trans compounds.

Alternatively, cis and trans compounds of the present invention can be prepared by the procedure of Figure 3. As shown in Figure 3, cyclohexene oxide can be reacted with alcohol (ROH) in the presence of Mg (C 104) 2 (see, for example, M. Chini et al., Snylett 673-676). , 1992) to give 1,2-hydroxycyclohexyl ether. Oxidation with pyridinium bromide (see, for example, R. Oshima et al., J. Org. Chem. 50, 2613-2621, 1985) gives the corresponding 1,2-alkoxycyclohexanone. Subsequent reductive amination (R.F. Borch et al., J. Am. Chem. Soc. 93 (12), 2987 2904, 1971) yields a mixture of cis and trans aminocyclohexyl ether. A mixture of diastereoisomeric ethers can be separated by a person skilled in the art by chromatography. The racemic cis or trans ether prepared can be separated by classical recrystallization, which is well known or by preparative chiral HPLC to give the individual enantiomers: trans- (1R, 2R), trans- (1S, 2S), cis- (1R, 2S) or cis - (lS, 2R) aminoethers.

The methods disclosed herein, particularly when combined with the general knowledge of this step, provide those skilled in the art with sufficient guidance for carrying out the synthesis, isolation and purification of the compounds of the present invention.

Means and routes of administration

In another embodiment, the present invention provides compositions comprising the compounds described in admixture or other association with one or more inert carriers, excipients and diluents, and optionally other optional ingredients. These compositions are suitable, for example, as testing standards, a convenient means of transferring large quantities, or as pharmaceuticals. The test amount of the compounds of the present invention is an amount that is readily measured by standard assay techniques well known to those skilled in the art. The test amount of the compounds of the present invention is generally from 0.001% to 75% by weight of the total composition.

Inert materials include all materials that do not undergo decomposition or other covalent reaction with the compounds of the present invention. Examples of suitable inert carriers are water, aqueous buffers (such as those used in HPLC); organic solvents such as acetonitrile, ethyl acetate, hexane and the like. (which are suitable for in vitro diagnosis or testing but are typically not suitable for administration to warm-blooded organisms); pharmaceutically acceptable carriers such as saline.

Thus, the present invention provides pharmaceutical or compositions (herein referred to collectively as pharmaceutical compositions) comprising the cyclohexylamine compounds described herein in admixture with a pharmaceutically acceptable carrier, excipient or diluent. The invention further provides a pharmaceutical composition comprising an effective amount of the disclosed cyclohexylamine compound in association with a pharmaceutically acceptable carrier.

The pharmaceutical compositions of the present invention may be in any form that allows the composition to be administered to patients. For example, the compositions may be in solid, liquid or gaseous (aerosol) form. Typical routes of administration include, without limitation, oral, topical, parenteral, subcutaneous, rectal, vaginal and intranasal administration. As used herein, the term parenterally includes subcutaneous injections, intravenous, intramuscular, epidural and intrastemal injection or infusion techniques. The pharmaceutical compositions of the present invention are in a form that allows the contained active ingredient to be bioavailable upon administration to the patient. The formulations to be administered to patients take the form of a single or multiple dosage unit, for example, a tablet, capsule or cachet may be a unit dose, and the container of the cyclohexylamine compound in aerosol form may contain many dosage units.

The substances used in the preparation of the pharmaceutical compositions must be pharmaceutically pure and nontoxic in the amounts used. The compositions of the present invention may contain one or more compounds (active ingredients) known for their particular desired effect. For example, it is possible to combine the epinephrine and the aminocyclohexyl ether compound of the present invention to provide a composition suitable for inducing local anesthesia. It will be appreciated by those skilled in the art that the optimum dose of the active ingredient in the pharmaceutical composition depends on many factors. Relevant factors include, but are not limited to, the type of patient (e.g., human), the particular form of the active ingredient, the mode of administration, and the compound employed.

The pharmaceutical composition generally comprises the cyclohexylamine compounds described herein in admixture with one or more carriers. The carrier may be particulate so that the composition is, for example, in the form of tablets or a powder. The carrier may also be liquid so that the composition is in the form of, for example, a syrup or a solution for injection. In addition, the carrier may be gaseous to provide an aerosol formulation suitable, for example, for administration by inhalation.

When the composition is for oral administration, it is preferably in solid or liquid form, including semisolid and semi-liquid mixtures, suspensions, and gels.

Solid compositions for oral administration may be in the form of powders, granules, compressed tablets, pills, capsules, cachets, chewing gums, caramel and the like. These solid compositions typically comprise one or more inert diluents or edible carriers. In addition, one or more of the following ingredients may be included: binders such as syrups, acacia, sorbitol, polyvinylpyrrolidone, carboxymethylcellulose, ethylcellulose, microcrystalline cellulose, gum tragacanth or gelatin and mixtures thereof, additives such as starch, lactose or dextrins, decomposition agents such as alginic acid, sodium alginate, Primogel, corn starch and the like; lubricants such as magnesium stearate or Sterotex: fillers such as lactose, mannitol, starch, calcium phosphate, sorbitol, methylcellulose and mixtures thereof, high molecular weight polymers such as polyethylene glycol, high molecular weight fatty acids such as stearic acid, silica gel, humectants such as for example sodium lauryl sulfate, talc flours such as diatomaceous earth; sweetening agents such as sucrose or saccharin; flavors such as peppermint, methyl salicylate or orange flavor; and coloring agents.

If the composition is in the form of, for example, gelatin capsules, it may contain, in addition to the aforementioned substances, a liquid carrier such as polyethylene glycol or an oil.

The composition may be in the form of a liquid, for example a beverage, syrup, solution, aqueous or oily emulsion or suspension, or a dry powder, which is dissolved in water or other liquid before administration. For example, the fluid may be for administration orally or by injection. If the composition is to be administered orally, it suitably contains one or more sweetening agents, fillers, preservatives (e.g., alkyl p-hydroxybenzoate), coloring agents and flavoring agents in addition to the listed compounds. The composition for injection may contain one or more surfactants, preservatives (e.g. alkyl-p-hydroxybenzoate), humectants, dispersants, suspending agents (e.g. sorbitol, glucose or other sweet syrup), buffers, stabilizers, and isotonic agents. The emulsifying agents may be selected from substances such as lecithin or sorbitol monooleate.

The liquid pharmaceutical compositions of the present invention (if they are to be solutions, suspensions, etc.) may contain one or more of the following ingredients: sterile diluents for injection such as water, saline, suitably saline, Ringer's solution, isotonic sodium chloride, stabilized oils, such as synthetic mono or diglycerides, which may serve as a solvent or suspending medium, polyethylene glycols, glycerin, propylene glycol, or other solvents; antibacterial agents such as benzyl alcohol or methylparaben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity such as sodium chloride or dextrose. The parenteral formulations may be enclosed in ampoules, disposable syringes or multiple dose vials of glass or plastic. A physiological saline is a preferred additive. Injectable pharmaceutical compositions are preferably sterile.

Liquid formulations for parenteral or oral administration contain an amount of the compounds of the present invention to achieve a suitable dosage. Typically, this amount is at least 0.01% of the compound of the present invention from the composition. For oral administration, this amount is from 0.1 to 70% by weight of the composition. Preferred oral compositions comprise from 4% to 50% active cyclohexylamine compound. Preferred compositions and formulations of the present invention are prepared so that a unit dose for parenteral administration contains from 0.01 to 10% by weight of the active compound.

The pharmaceutical compositions may be for topical administration. In this case, the carrier is a solution, emulsion, ointment, cream or gel. The carrier base may comprise one or more of vaseline, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers. Thickeners may be present in the compositions for topical administration. Compositions for transdermal administration may include transdermal patches or an ointment. The topical compositions may contain the compounds of the present invention at a concentration of from 0.1 to 25% w / v.

The compositions for rectal administration may, for example, be in the form of suppositories that melt in the rectum and release the drug. Formulations for rectal administration may contain an oily base (as a suitable non-irritant). These bases include, but are not limited to, lanolin, cocoa butter, and polyethylene glycol. For preparing suppositories, low melting waxes are suitable wherein the wax is a mixture of fatty acid glycerides and / or cocoa butter. The waxes are melted and the cyclohexylamine compound is uniformly dispersed therein. The molten mixture is then poured into a mold of suitable shape and allowed to cool and solidify.

The composition may contain various substances which modify the physical properties of the solid or liquid dosage form. For example, the composition may contain substances which form a sheath around the active ingredient. They are typically inert substances from the group consisting of, for example, sugar, shellac and other intestinal coating agents. Alternatively, the active ingredient may be enclosed in a gelatin capsule or wafer.

The composition, in solid or liquid form, may contain an agent that binds to the cyclohexylamine compound to help deliver the active ingredient. Suitable agents that can do this are monoclonal or polyclonal antibodies and proteins or liposomes.

The pharmaceutical compositions of the present invention may be gaseous, for example in the form of an aerosol. The term aerosol is used to refer to various systems ranging from colloidal to pressurized containers. The carrier can be a liquefied or compressed gas, or a suitable nebulizer that dispenses the active ingredients. The aerosols of the present invention may be in the form of a single-phase, two-phase, or three-phase system. The aerosol composition is comprised of a container, an activator, valves, an inner container, and the like, which together form a kit. Those skilled in the art are aware of aerosol formulations, no experiments are necessary.

The pharmaceutical compositions of the present invention may comprise one or more known pharmacological agents used to modulate ion channel activity in warm-blooded organisms or to modulate ion channel activity in vitro, or used to treat arrhythmias, central nervous system disorders, seizures, epileptic seizures, depression, anxiety , schizophrenia, Parkinson's disease, respiratory problems, cystic fibrosis, asthma, cough, inflammation, arthritis, allergy, gastrointestinal disorders, urinary incontinence, irritable bowel syndrome, cardiovascular disease, cerebral or cardiac ischcmic, hypertension, hypertension, hypertension, hypertension, hypertension ophthalmological diseases, diabetes mellitus, myopathy, Becker's myotonia, myasthenia gravis, congenital paramyotonia, malignant hyperthermia, hypercalcemic periodic paralysis, Thomsen myotonia, autoimmune disorders, from transplantation of the transplanted organ or bone marrow, heart failure, hypotension, Alzheimer's disease or other metal and alopecia disorders. Other agents known to ameliorate libido, topical analgesics or anesthetics may also be combined with the compounds of the present invention.

The pharmaceutical compositions may be prepared by a methodology well known in the art of pharmaceutical technology. The aminocyclohexyl compounds of the present invention may be in the form of a solvate in a pharmaceutically acceptable solvent, such as water or saline. Alternatively, the compounds may be in the form of the free base or in the form of a pharmaceutically acceptable salt, such as hydrochloride, sulfate, phosphate, citrate, famaran, methanesulfonate, acetate, tartrate, maleate, lactate, malate, salicylate, succinate and other salts known in the art. The appropriate salt is selected to improve the bioavailability or stability of the compound for a given mode of use (e.g., for oral or parenteral administration).

The composition for injection may be prepared by combining the cyclohexylamine compound with water and suitably a buffer to form a solution. The water should be sterile and pyrogen-free. A surfactant may be added to form a homogeneous solution or suspension. Surfactants are compounds that interact non-covalently with the cyclohexylamine compound to allow for the dissolution or formation of a homogeneous suspension of the cyclohexylamine compound in an aqueous environment. Surfactants are desirable in the aqueous compositions of the present invention since the cyclohexylamine compounds of the present invention are typically hydrophobic. Other carriers for injection include, without limitation, sterile peroxide-free ethyl acetate, dehydrated alcohols, propylene glycol, and mixtures thereof.

Suitable pharmaceutical excipients for injection include stabilizers, solubilizers, buffers, and viscosity regulators. Examples of such additives are ethanol, ethylenediaminetetraacetic acid (EDTA), tartrate buffers, citrate buffers, and high molecular weight polyethylene oxide viscosity regulators. These pharmaceutical compositions may be injected intramuscularly, epidurally, intraperitoneally or intravenously.

Pharmacological tests

As described, the present invention for the use of the disclosed compounds provides methods for both in vitro and in vivo use. In one embodiment, ion channels, such as cardiac sodium channels, are blocked in vitro and in vivo.

Ion channels are ubiquitous membrane proteins of cells of warm-blooded animals, such as mammals. Their critical physiological tasks include controlling electrical potential across the membrane, ion and flow equilibria, assisting neuromuscular and neuronal transmission, fast signaling across the membrane, and regulating secretion and contraction.

Therefore, compounds capable of modulating the activity or function of the respective ion channels are useful in the treatment or prevention of many diseases or disorders caused by poor or insufficient ion channel function. The compounds of the present invention are very active in modulating ion channel activity both in vivo and in vitro.

In another embodiment, the disclosed compound is used to treat arrhythmia. The term "treating arrhythmia" refers to both treatment and prevention (both advanced and initial arrhythmia). An effective amount of a composition of the present invention is used to treat arrhythmias in warm-blooded animals, including humans. Methods of administering an effective amount of antiarrhythmic agents are well known. They include oral or parenteral administration. Dosage forms include, but are not limited to, parenteral dosage forms. Such forms include, but are not limited to, parenteral solutions, tablets, capsules, slow release implants, and transdermal delivery systems. Oral or intravenous administration is generally preferred. The amount and frequency of administration is selected so as to achieve an effective level of the agent without hazardous effects. The dose generally ranges from 0.1 to 100 mg / kg / day, typically from 0.1 to 10 mg / kg, when administered orally or intravenously to produce an antiarrhythmic effect.

The compositions of the present invention may also be administered in combination with other agents. For example, it may be desirable to administer anti-opioid agents such as naloxone (if the compound has opioid activity where this is not desired). Naloxone may counteract the opium activity of the administered compound without adversely affecting the antiarrhythmic activity. Another example is epinephrine (for local anesthesia).

In order to determine whether a compound has the desired pharmacological activity of the present invention, it is subjected to a number of assays. The particular test used depends on the physiological response that interests us. The published literature contains many procedures for testing the efficacy of a potential therapeutic agent that can be used for the compounds and compositions of the present invention.

A series of four tests may be performed to treat or prevent arrhythmia. In the first, the compound of the present invention is administered in increasing dose (2 trials with each dose) intravenously every 8 minutes to rats under pentobarbital anesthesia. After each dose at intervals of 1, 2, 4 and 8 minutes, the effect of the compounds on blood pressure, heart rate and ECG is measured for 30 seconds. The dose is increased until the animal dies. In any case, the cause of death is determined - it is either respiratory or cardiac. This test determines whether the compound modulates sodium or potassium channel activity as well as acute toxicity. The index of sodium channel blockade is the increasing P-R interval and QRS spread in the ECG. Potassium channel blockade leads to Q-T interval prolongation in ECG.

The second test involves the administration of the compound as an infusion to rats under pentobarbital anesthesia whose left ventricle is subjected to electrical stimulation (a detailed description is given). The procedure involves establishing a threshold for the induction of extrasystole and ventricular fibrillation. Furthermore, the effects on electrical resistance (single strike technique) are determined. At the same time, the effect on blood pressure, heart rate and ECG is recorded. In this assay, sodium channel blockade produces the changes in ECG expected by the first assay. In addition, sodium channel blockade will increase the boundaries of extrasystole induction and ventricular fibrillation. Potassium channel blockade results in increased resistance and widening of Q-T ECG intervals.

In a third test, isolated rat heart is treated with increasing concentration of compound. Ventricular pressures, heart rate, conductivity rate and ECG are measured in the presence of various concentrations of the compound. The test will provide information on direct myocardial toxicity. At the same time, the selectivity, potency and potency of the compound under conditions simulating ischemia can be ascertained. The effective concentrations found in this test are considered effective in electrophysiological studies.

The fourth test is an estimate of the antiarrhythmic activity of the compounds against arrhythmia induced by occlusion of rat coronary artery under anesthesia. Suitable antiarrhythmic compounds are expected to have antiarrhythmic activity at a dose that has minimal effect on ECG, blood pressure or heart rate (under normal conditions).

All previous tests are performed with rat tissue. Further tests in dogs and primates are performed to determine whether the compounds have specific effects on rat tissue. In order to determine the possible blocking effect on the sodium and potassium channels in vivo in dogs, the compound is tested for effects on ECG, ventricular rate of epicardial conductivity, and response to electrical stimulation. To reduce the left ventricular epicardium, the dog's chest is anesthetized. After removal of the pericardium, a sensing / pacing electrode is sewn to the left ventricular epicardium surface. In this way, appropriate stimulation protocols, the rate of conduction through the epicardium, and the response to electrical stimulation can be ascertained. This ECG-related information makes it possible to determine whether a sodium and / or potassium channel is blocked. As in the first assay, the compound is administered as a series of increasing doses. At the same time, the possible toxic effects of the compounds on the dogs cardiovascular system are determined.

The effects of the compounds on ECG and responses to electrical stimulation were also determined in baboons (Papio anubis) under halothane anesthesia. The baboon is anesthetized with a blood pressure cannula and ECG electrodes. A stimulation electrode is placed on the first chamber together with a monophasic action potential electrode. As in the above assay, ECG and electrical stimulation responses for each compound show the possible presence of sodium and / or potassium channel blockade. At the same time, the monophasic action potential indicates whether the compound expands the action potential, which is the expected effect of potassium channel blockade.

As another example of alleviating or preventing pain, the following test may be performed. To determine the effect of the compounds of the present invention on the response of the animals to a sharp pain sensation, the effect of a small puncture of a 7.5 g weighing syringe with a 23G needle in a shaved guinea pig back (Cavia poreellus) is determined after subcutaneous administration of sufficient solution of the compound in saline, causing a visible blister on the skin. Each test is performed at the center and also at the edge of the blister to determine the diffusion of the test solution from the administration site. If the test animal grins after irritation, this demonstrates the absence of a blockage of pain. Testing was performed at intervals up to 4 hours after administration. The blister site is checked after 24 hours and has no changes due to local administration of the test compound or saline (which is the carrier used to prepare the test samples).

Other means

The present invention also provides kits comprising pharmaceutical compositions comprising one or more compounds of the above formula. The kit also includes instructions for using a pharmaceutical composition for modulating ion channel activity, for treating arrhythmia or achieving local analgesia and / or anesthesia, and for other uses disclosed herein. The commercial package preferably comprises one or more dosage units of the pharmaceutical composition. For example, the dosage unit may be in an amount sufficient to prepare an intravenous injection. It will be appreciated by those skilled in the art that light and / or air sensitive compounds may require special packaging and / or forms. For example, it is possible to use a package that is opaque and / or tight so as to avoid contact with ambient air and / or in a form with a suitable coating substance or additive.

DETAILED DESCRIPTION OF THE INVENTION

The following examples are given to illustrate the invention and not to limit it. Unless otherwise stated, starting materials in the examples are obtained from well-known commercial sources such as Aldrich Chemical Company (Milwaukee, WI). Purity is standard. The terms "ether" and "ethyl ether" refer to diethyl ether: "h" refers to hours; "Min." Means minutes: "GC" means gas chromatography; 'By volume' means the volume ratio; ratios are (unless otherwise indicated) weight ratios.

Example 1

(±) - trans- [2- (4-Morpholinyl) -1- (2-naphthenethoxy)] cyclohexane monohydrochloride (Compound No. 1) (i) A mixture of 5 ml morpholine (57 mmol), 5.8 ml cyclohexene oxide (57 mmol) and 3 ml of water are heated at reflux for 1.5 hours. The reaction was complete by gas chromatography. The cooled mixture was partitioned between saturated sodium hydroxide solution (50 ml) and ether (75 ml). The aqueous layer was washed with 30 mL of ether and the combined ether layers were dried over sodium sulfate. The ether was removed in vacuo to give 9.83 g of a yellow oil. The crude (±) - [methyl] - [2- (4-morpholinyl)] cyclohexanol is purified by vacuum distillation (b.p. 75-80 ° C under full vacuum) to give 8.7 g of a clear solution. Yield 82.5%.

(ii) To a cooled (0 ° C) solution of 6.0 g of (±) -trans- [2- (4-morpholinyl)] cyclohexanol (32.4 mmol) and 6.8 mL of triethylamine (48 mmol) in 100 mL A solution of 3.10 mL of methanesulfonyl chloride (40 mmol) in 50 mL of dichloromethane was added via syringe. The addition was carried out for 10 minutes and the reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature for 4 hours. The dichloromethane mixture was washed twice with 50 ml of water and the combined aqueous layers were extracted with 50 ml of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 8.5 g (100% yield) of crude mesylate.

(iii) To a solution of 1.24 g of sodium hydride (80% oil dispersion washed three times with 20 ml of hexane, 51.6 mmol) in 50 ml of dry dimethylformamide was added a solution of 6.8 g of 2-naphthenethanol (40 mmol) in 50 ml. of dry dimethylformamide. Upon addition, the gas evolved, the reaction mixture was stirred at room temperature and passed to a gel. The mesylate prepared in (ii) is dissolved in 50 ml of dimethylformamide and the solution is quickly added by syringe to the alcoholate slurry. The reaction mixture is heated to 80 ° C and then the temperature is lowered to 40 ° C. The resulting yellow solution was poured into 1500 ml of ice-water and extracted three times with 300 ml of ethyl acetate. The combined organic extracts were washed with saturated brine (500 ml) and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 13.4 g of an amber oil which was dissolved in 150 ml of water and the pH of the solution was adjusted to 2 by addition of aqueous 1M hydrochloric acid. The acidic aqueous solution is extracted twice with 100 ml of ether and then the pH is adjusted to 10 by addition of 50% aqueous sodium hydroxide solution. The basic aqueous solution was extracted twice with 100 mL of ether, the combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 7.16 g of crude free amino ether. The crude product is purified by chromatography on silica gel 60 (70-230 mesh) in ethyl acetate-chloroform (1: 1 by volume) to give 4.37 g of pure free base. The product was dissolved in 80 ml of ethyl ether and converted to the monohydrochloride salt by adding a saturated solution of hydrogen chloride in 80 ml of ether. An oil precipitated out of the solution, the solvent was evaporated in vacuo and the residue dissolved in a minimum amount of warm ethyl alcohol. Addition of a large amount of ether triggers crystallization. The crystals were collected to give 3.83 g (31% yield) of the title compound. Mp 158-160 ° C, elemental analysis is given in Table 1.

Example 2

(±) - trans - [2- (4-Morpholinyl) -1- (1-naphthenethoxy) cyclohexane monohydrochloride (Compound No. 2) (i) The starting transaminocyclohexanol was prepared according to Example 1.

(ii) To a cooled (0 ° C) solution of 6.0 g of (±) - trans - [2- (4-morpholinyl)] cyclohexanol (32 mmol) and 6.8 mL of triethylamine (48 mmol) in 100 mL of dichloromethane was added. a solution of 3.10 mL of methanesulfonyl chloride (40 mmol) in 50 mL of dichloromethane was added via syringe. The addition was carried out for 10 minutes and the reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature for 4 hours. The dichloromethane mixture was washed twice with 50 ml of water and the combined aqueous layers were extracted with 50 ml of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 9.0 g of crude mesylate.

(iii) To 1.30 g of sodium hydride (80% oil dispersion washed three times with 20 ml of hexane, 51.6 mmol) in 50 ml of dimethylformamide was added a solution of 6.8 g of 1-naphthenethanol (40 mmol) in 50 ml of dry dimethylformamide. . After the addition gas evolved and the reaction mixture was stirred at room temperature for 4 hours. The mesylate prepared in (ii) is dissolved in 50 ml of dry dimethylformamide and the resulting solution is added rapidly (3 min.) To a slurry of alcoholate by syringe. The reaction mixture was heated at 80 ° C for 3 hours and then the temperature was lowered to 35 ° C and stirring was continued overnight. The reaction mixture was poured into 1500 ml of ice-water and extracted three times with 300 ml of ethyl acetate. The combined organic extracts were washed with saturated brine (500 ml) and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 12.0 g of an oil which was dissolved in 80 mL of ether. A saturated solution of hydrogen chloride in ether was then added and the solid precipitated out of solution. The solvent was evaporated in vacuo and the resulting crude hydrochloride was dissolved in 200 mL of water. The acidic aqueous solution is extracted twice with 100 ml of ether and then the pH is adjusted to 10 by addition of 50% aqueous sodium hydroxide solution. The basic aqueous solution was extracted twice with 100 mL of ether and the combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 7.20 g of crude free amino ether. The crude product is purified by chromatography on silica gel 60 (70-230 mesh) in ethyl acetate-dichloromethane (1: 1 by volume) to give the pure free base. The product was dissolved in ether (80 ml) and converted to the monohydrochloride salt by adding a saturated solution of hydrogen chloride in ether (80 ml). A white product precipitated, which was collected and dissolved in a minimum amount of warm ethyl alcohol. Addition of a large amount of ether begins to crystallize. The crystals were collected to give 2.30 g of the title compound, m.p. 198-200 ° C. Elemental analysis is shown in Table 1.

Example 3

(±) - trans - [2- (4-Morpholinyl) -1- (4-bromophenethoxy) cyclohexane monohydrochloride, (compound 3) (i) The starting transaminocyclohexanol was prepared according to Example 1.

(ii) To a cooled (0 ° C) solution of 3.0 g of (±) - trans - [2- (4-morpholinyl)] cyclohexanol (16.2 mmol) and 3.4 mL of triethylamine (24 mmol) in A solution of 1.55 mL of methanesulfonyl chloride (20.0 mmol) in 25 mL of dichloromethane was added via syringe with 25 mL of dichloromethane. Addition takes place over 5 minutes. The reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature for 2 hours. It is then diluted with 50 ml of dichloromethane and washed twice with 50 ml of water. The combined aqueous layers were extracted with 25 mL of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 4.7 g of the crude mesylate.

(iii) To a solution of 0.62 g sodium hydride (80% oil dispersion washed three times with 10 ml hexane, 25.8 mmol) in 25 ml dry dimethylformamide was added a solution of 4.0 g 4-bromophenethyl alcohol (20 mmol) in 50 ml. dimethylformamide. After the addition gas evolved and the reaction mixture was stirred at room temperature for 4 hours. The mesylate prepared in (ii) is dissolved in 50 ml of dry dimethylformamide and the resulting solution is added rapidly (3 min.) To a slurry of alcoholate by syringe. The reaction mixture was heated at 80 ° C for 2 hours and then the temperature was lowered to 35 ° C and stirring was continued overnight. The reaction mixture was poured into 800 mL of ice-water and extracted three times with 200 mL of ethyl acetate. The combined organic extracts were washed with 150 ml of saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 7.4 g of an oil which was dissolved in 80 ml of ether. A saturated solution of hydrogen chloride in ether was then added and an oil precipitated from the solution. The solvent was evaporated in vacuo and the residue was dissolved in 100 ml of water. The acidic aqueous solution is extracted twice with 50 ml of ether and then the pH is adjusted to 10 by addition of 50% aqueous sodium hydroxide solution. The basic aqueous solution was extracted twice with 50 mL of ether and the combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 3.67 g of crude free amino ether. The crude product is purified by chromatography on silica gel 60 (70-230 mesh) in ethyl acetate-dichloromethane (1: 1 by volume) to give the pure free base. The product was dissolved in ether (30 ml) and converted to the monohydrochloride salt by adding a saturated solution of hydrogen chloride in ether (30 ml). The solvent was evaporated and the residue was dissolved in a minimum amount of ethyl alcohol. The desire for a large amount of ethyl ether begins to crystallize. The crystals were collected to give 1.31 g of the title compound, m.p. 148-151 ° C. Elemental analysis is shown in Table 1.

Example 4

(±) -Rrazis- [2- (4-morpholinyl) -1- [2- (2-naphthoxy) ethoxy] cyclohexane monohydrochloride, (Compound No. 4) (i) The starting transaminocyclohexanol was prepared according to Example 1.

(ii) To a cooled (0 ° C) solution of 3.0 g of (±) -trans- [2- (4-morpholinyl)] cyclohexanol (16.2 mmol) and 3.4 mL of triethylamine (24 mmol) in 50 mL A solution of 1.55 mL of methanesulfonyl chloride (20.0 mmol) in 50 mL of dichloromethane was added via syringe. Addition was performed for 10 minutes. The reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature for 4 hours. The dichloromethane solution was washed twice with 50 ml of water. The combined aqueous layers were extracted with 50 mL of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 4.3 g of crude mesylate.

(iii) To a solution of 0.7 g of sodium hydride (80% oil dispersion washed three times with 10 ml of hexane, 29 mmol) in 50 ml of dry dimethylformamide was added a solution of 3.76 g of 2- (2-naphthoxy) alcohol (20 mmol). in 50 ml of dry dimethylformamide. Upon addition, the gas evolved and the reaction mixture was stirred at room temperature for 1.5 hours. The mesylate prepared in (ii) is dissolved in 50 ml of dry dimethylformamide and the resulting solution is added rapidly (3 min.) To the above reaction mixture by syringe. The reaction mixture was heated at 90 ° C overnight and then the temperature was lowered to room temperature. The reaction mixture was poured into ice-water (800 ml) and extracted with ethyl acetate (3.times.200 ml). The combined organic extracts were washed with 300 mL of saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 7.8 g of a yellow oil which was dissolved in 100 ml of ether. 100 ml of a saturated solution of hydrogen chloride in ether are then added. The resulting precipitate was collected, partially solubilized in 200 mL of water, and the heterogeneous mixture was extracted twice with 100 mL of ether. The remaining insoluble material is collected and recrystallized in 75 ml of boiling ethanol to give the first portion of the desired product. The pH of the acidic aqueous solution was adjusted to 10 by adding 50 aqueous sodium hydroxide solution. The basic aqueous solution was extracted twice with 50 mL of ether and the combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 1.6 g of crude free amino ether. The crude product is purified by chromatography on silica gel 60 (70-230 mesh) in ethyl acetate-dichloromethane (1: 1 by volume) to give pure 0.73 g of a pale yellow oil. The pure free base is then dissolved in 50 ml of ether and converted to the monohydrochloride by addition of a saturated solution of hydrogen chloride in 50 ml of ether. The white precipitate was recrystallized in 40 ml of boiling ethanol to give a second crop of product. Combine both to give 1.03 g of the title compound, mp 235-237 ° C. Elemental analysis is shown in Table 1.

Example 5

(±) - trans - [2- (4-Morpholinyl) -1- [2- (4-bromophenoxy) ethoxy]] cyclohexane monohydrochloride, (Compound No. 5) (i) The starting transaminocyclohexanol was prepared according to Example 1.

(ii) To a cooled (0 ° C) solution of 3.0 g of (±) - trans - [2- (4-morpholinyl)] cyclohexanol (16.2 mmol) and 3.4 mL of triethylamine (24 mmol) in 50 mL of dichloromethane was added a solution of 1.55 mL of methanesulfonyl chloride (20.0 mmol) in 50 mL of dichloromethane via syringe. Addition was carried out for 10 minutes. The reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature for 4 hours. The dichloromethane solution was washed twice with 50 ml of water. The combined aqueous layers were extracted with 50 mL of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 3.95 g (92% yield) of the crude mesylate.

(iii) To a solution of 0.63 g of sodium hydride (80% oil dispersion washed three times with 10 ml of hexane, 26 mmol) in 50 ml of dry dimethylformamide was added a solution of 4.34 g of 2- (4-bromophenoxy) ethanol (20 mmol). in 50 ml of dry dimethylformamide. Upon addition, the gas evolved and the reaction mixture was stirred at room temperature for 1.5 hours. The mesylate prepared in (ii) is dissolved in 50 ml of dry dimethylformamide and the resulting solution is added rapidly (3 min.) To the above reaction mixture by syringe. The reaction mixture was heated to 90 ° C for 90 minutes and then the temperature was lowered to 40 ° C and stirred overnight. The reaction mixture was poured into 800 ml of ice-water and extracted three times with 200 ml of ethyl acetate. The combined organic extracts were washed with 300 mL of saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 8.35 g of a yellow oil which was dissolved in 100 ml of ether. 100 ml of a saturated solution of hydrogen chloride in ether are then added. A white solid precipitated which was collected and recrystallized in 150 ml of boiling ethanol to give 3.7 g (yield 54%) of the pure title compound, mp 228-230 ° C. Elemental analysis is shown in Table 1.

Example 6

(±) - trans- [2- (4-Morpholinyl) -1- (3,4-dimethoxyphenethoxy)] cyclohexane monohydrochloride (Compound No. 6) (i) The starting transaminocyclohexanol was prepared according to Example 1.

(ii) To a cooled (0 ° C) solution of 3.0 g of (±) -traris- [2- (4-morpholinyl)] cyclohexanol (16.2 mmol) and 3.4 mL of triethylamine (24 mmol) in 50 mL A solution of 1.55 mL of methanesulfonyl chloride (20.0 mmol) in 50 mL of dichloromethane was added via syringe. Addition was performed for 10 minutes. The reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature for 4 hours. The dichloromethane solution was washed twice with 50 ml of water. The combined aqueous layers were extracted with 50 mL of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 4.18 g of crude mesylate.

(iii) To a solution of 0.64 g of sodium hydride (80% oil dispersion washed three times with 10 ml of hexane, 27 mmol) in 50 ml of dry dimethylformamide was added a solution of 3.64 g of 3,4-dimethoxyphenethyl alcohol (20 mmol) in 50 ml. of dry dimethylformamide. Upon addition, the gas evolved and the reaction mixture was stirred at room temperature for 1.5 hours. The mesylate prepared in (ii) is dissolved in 50 ml of dry dimethylformamide and the resulting solution is added rapidly (3 min.) To the above reaction mixture by syringe. The reaction mixture was heated to 80 ° C for 90 minutes and then the temperature was lowered to 40 ° C and stirred overnight. The reaction mixture was poured into ice-water (800 ml) and extracted with ethyl acetate (3.times.200 ml). The combined organic extracts were washed with 300 mL of saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 7.18 g of crude product which was dissolved in 100 mL of ether. 100 ml of a saturated solution of hydrogen chloride in ether are then added. The solvent is evaporated in vacuo and the residual oil is taken up in 100 ml of water and extracted twice with 50 ml of ether. The aqueous layer was adjusted to pH 10 by addition of 50% aqueous sodium hydroxide solution and extracted twice with 50 ml of ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product is purified by chromatography on silica gel 60 (70-230 mesh) in ethyl acetate-dichloromethane (1: 1 by volume) to give 2.8 g of a pale yellow oil. The free base is then dissolved in 80 ml of ether and converted to the monohydrochloride by addition of 80 ml of a saturated solution of hydrogen chloride in ether. The solid precipitate was collected, dissolved in a minimum amount of ethanol, and a large excess of ether was added to begin crystallization of 2.24 g (yield 36%) of the title compound, mp 148-150 ° C. Elemental analysis is shown in Table 1.

Example 7

(±) - trans - [2- (1-Pyrrolidinyl) -1- (1-naphthethoxy)] cyclohexane monohydrochloride (Compound No. 7) (i) A mixture of 25 ml of pyrrolidine (300 mmol), 30 ml of cyclohexene oxide (297 mmol) ) and 10 ml of water are heated to boiling for 3 hours. The reaction was complete by gas chromatography. The cooled mixture was partitioned between saturated sodium hydroxide solution (10 ml) and ether (150 ml). The aqueous layer was washed twice with 10 mL of ether and the combined ether layers were dried over sodium sulfate. The ether was removed in vacuo to give a yellow oil. The crude product is purified by vacuum distillation, boiling point 66-69 ° C under full vacuum. 43.9 g of a clear liquid are obtained. Yield 87%.

(ii) To a cooled (0 ° C) solution of 2.74 g of (±) trans [2-pyrrolidinyl)] cyclohexanol (16.2 mmol) and 3.4 mL of triethylamine (24 mmol) in 50 mL of dichloromethane was added a solution 1.55 ml of methanesulfonyl chloride (20.0 mmol) in 50 ml of dichloromethane. Addition was performed for 10 minutes. The reaction mixture was washed twice with 50 ml of water and the combined aqueous layers were extracted with 50 ml of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 3.24 g of crude mesylate.

(iii) To a solution of 0.64 g of sodium hydride (80% oil dispersion washed three times with 10 ml of hexane, 27 mmol) in 50 ml of dry dimethylformamide was added a solution of 3.64 g of 1-naphthenethanol (20 mmol) in 50 ml of dry dimethylformamide. . Upon addition, the gas evolved and the reaction mixture was stirred at room temperature for 1.5 hours. The mesylate prepared in (ii) is dissolved in 50 ml of dry dimethylformamide and the resulting solution is added rapidly (3 min.) To the above reaction mixture by syringe. The reaction mixture was heated to 80 ° C for 90 minutes and then the temperature was lowered to 40 ° C and stirred overnight. The reaction mixture was poured into ice-water (800 ml) and extracted with ethyl acetate (3.times.200 ml). The combined organic extracts were washed with 300 mL of saturated sodium chloride solution and dried over sodium sulfate.

Evaporation of the solvent in vacuo gave 9.00 g of crude product, which was dissolved in 50 mL of ether. 50 ml of a saturated solution of hydrogen chloride in ether are then added. The solvent is evaporated in vacuo and the residual oil is taken up in 100 ml of water and extracted twice with 50 ml of ether. The aqueous layer was adjusted to pH 10 by addition of 50% aqueous sodium hydroxide solution and extracted twice with 50 ml of ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product is purified by chromatography on silica gel 60 (70-230 mesh) in methanol / chloroform (2: 8 by volume). The free amino ether is partially dissolved in 80 ml of ether, the solid is filtered off and then 80 ml of a saturated solution of hydrogen chloride in ether is added to the filtrate. The solvent was evaporated in vacuo, the residue was dissolved in acetone and the addition of an equal volume of ether started to crystallize slowly. Both portions of the title compound were combined to give 0.88 g of product, mp 103-105 ° C. Elemental analysis is shown in Table 1.

Example 8

(±) -trans- [2- (4-Morpholinyl) -1- [benzo [b] thiophen-3-yl) ethoxy] cyclohexane monohydrochloride, (Compound No. 8) (i) The starting transaminocyclohexanol was prepared according to Example 1 .

(ii) To a cooled (0 ° C) solution of 3.0 g of (±) -trans- [2- (4-morpholinyl)] cyclohexanol (16.2 mmol) and 3.4 mL of triethylamine (24 mmol) in 50 mL A solution of 1.55 mL of methanesulfonyl chloride (20.0 mmol) in 50 mL of dichloromethane was added via syringe. Addition takes place over 5 minutes. The reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature for 3 hours. The reaction mixture is washed three times with 30 ml of water. The combined aqueous layers were extracted with 50 mL of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 5.25 g of crude mesylate.

(iii) To a solution of 0.60 g of sodium hydride (80% oil dispersion washed three times with 10 ml of hexane, 25 mmol) in 50 ml of dry dimethylformamide was added a solution of 3.56 g of 2- (benzo [b] thiophen-3-yl). of ethanol (20 mmol) in 50 mL of dry dimethylformamide. After the addition gas evolved and the reaction mixture was stirred at room temperature for 3 hours. The mesylate prepared in (ii) is dissolved in 50 ml of dry dimethylformamide and the resulting solution is added rapidly (2 min.) To the above reaction mixture by syringe. The reaction mixture was heated at 75 ° C for 2 hours and then the temperature was lowered to 65 ° C and stirred overnight. The reaction mixture was poured into ice-water (800 ml) and extracted with ethyl acetate (3.times.200 ml). The combined organic extracts were washed with 300 mL of saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 7.7 g of crude product which was dissolved in 100 mL of ether. 100 ml of a saturated solution of hydrogen chloride in ether are then added. An oil precipitates from the solution, the solvent is evaporated in vacuo and the resulting crude hydrochloride is dissolved in 200 ml of water. The acidic aqueous solution is extracted twice with 100 ml of ether and the pH is then adjusted to 10 by addition of 50% aqueous sodium hydroxide solution and extracted three times with 100 ml of ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 3.30 g of crude amino ether. The crude product is purified by chromatography on silica gel 60 (70-230 mesh) in ethyl acetate / dichloromethane (1: 1, v / v) to give the free base. The product is dissolved in 100 ml of ether and converted to the monohydrochloride by addition of 100 ml of a saturated solution of hydrogen chloride in ether. The solvent was evaporated in vacuo and the residue was dissolved in a minimum of boiling methanol. After cooling, a first crop of 0.7 g was obtained. Addition of ether to the methanol filtrate gave a second crop of 0.55 g. Combine both portions to give 1.25 g of the title compound, m.p. 158-160 ° C. Elemental analysis is shown in Table 1.

Example 9

(±) -trans- [2- (4-Morpholinyl) -1- [2-benzo [b] thiophen-4-yl) ethoxy] cyclohexane monohydrochloride, (Compound No. 9) (i) The starting transaminocyclohexanol is prepared according to of Example 1.

(ii) To a cooled (0 ° C) solution of 3.0 g of (±) - trans [2- (4-morpholinyl)] cyclohexanol (16.2 mmol) and 3.4 mL of triethylamine (24 mmol) in 50 mL of water. A solution of 1.55 mL of methanesulfonyl chloride (20.0 mmol) in 50 mL of dichloromethane was added via syringe. Addition takes place over 5 minutes. The reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature for 3 hours. The reaction mixture was washed twice with 30 ml of water. The combined aqueous layers were extracted with 50 mL of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 4.24 g of crude mesylate.

(iii) To a solution of 0.60 g of sodium hydride (80% oil dispersion washed three times with 10 ml of hexane, 25 mmol) in 50 ml of dry dimethylformamide was added a solution of 3.56 g of 2- (benzo [b] thiophen-4-yl). of ethanol (20 mmol) in 50 mL of dry dimethylformamide. After the addition gas evolved and the reaction mixture was stirred at room temperature for 3 hours. The mesylate prepared according to (ii) is dissolved in 50 ml of dry dimethylformamide and the resulting solution is added rapidly (2 min) by syringe to said Teat mixture. The reaction mixture was heated at 85 ° C for 2 hours and then the temperature was lowered to 40 ° C and stirred overnight. The reaction mixture was poured into ice-water (800 ml) and extracted with ethyl acetate (3.times.200 ml). The combined organic extracts were washed with 300 mL of saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 8.2 g of an oil which was dissolved in 100 mL of ether. 100 ml of a saturated solution of hydrogen chloride in ether are then added. An oil precipitates from the solution, the solvent is evaporated in vacuo and the resulting crude hydrochloride is dissolved in 200 ml of water. The acidic aqueous solution is extracted twice with 100 ml of ether and the pH is then adjusted to 10 by addition of 50% aqueous sodium hydroxide solution and extracted three times with 100 ml of ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 3.0 g of crude amino ether. The crude product is purified by chromatography on silica gel 60 (70-230 mesh) in ethyl acetate / dichloromethane (1: 1, v / v) to give the free pure base. The product is dissolved in 50 ml of ether and converted to the monohydrochloride by addition of 50 ml of a saturated solution of hydrogen chloride in ether. The solvent was evaporated in vacuo and the residue was dissolved in a minimum of cold ethanol. Addition of ether begins to form crystals. 1.17 g of product with a melting point of 178 DEG-180 DEG C. are obtained. Elemental analysis is shown in Table 1.

Example 10

(±) - / trans - [2- (4-Morpholinyl) -1- (3-bromophenethoxy)] cyclohexane monohydrochloride (Compound No. 10) (i) The starting transaminocyclohexanol is prepared according to Example 1.

(ii) To a cooled (0 ° C) solution of 3.0 g of (±) -trans- [2- (4-morpholinyl)] cyclohexanol (16.2 mmol) and 3.4 mL of triethylamine (24 mmol) in 50 mL A solution of 1.55 mL of methanesulfonyl chloride (20.0 mmol) in 50 mL of dichloromethane was added via syringe. Addition takes place over 5 minutes. The reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature for 3 hours. The reaction mixture was washed twice with 30 ml of water. The combined aqueous layers were extracted with 50 mL of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 5.4 g of the crude mesylate.

(iii) To a solution of 0.60 g sodium hydride (80% oil dispersion washed three times with 10 ml hexane, 25 mmol) in 50 ml dry dimethylformamide was added a solution of 4.00 g 3-bromophenethyl alcohol (20 mmol) in 50 ml dry dimethylformamide. . After the addition gas evolved and the reaction mixture was stirred at room temperature for 3 hours. The mesylate prepared in (ii) is dissolved in 50 ml of dry dimethylformamide and the resulting solution is added rapidly (2 min) to the above reaction mixture by syringe. The reaction mixture was heated at 85 ° C for 2 hours and then the temperature was lowered to 40 ° C and stirred overnight. The reaction mixture was poured into ice-water (800 ml) and extracted with ethyl acetate (3.times.200 ml). The combined organic extracts were washed with 300 mL of saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 8.0 g of an oil which was dissolved in 100 mL of ether. 100 ml of a saturated solution of hydrogen chloride in ether are then added. An oil precipitates from the solution, the solvent is evaporated in vacuo and the resulting crude hydrochloride is dissolved in 200 ml of water. The acidic aqueous solution is extracted twice with 100 ml of ether and the pH is then adjusted to 10 by addition of 50% aqueous sodium hydroxide solution and extracted three times with 100 ml of ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 2.9 g of crude free aminoether. The crude product is purified by chromatography on silica gel 60 (70-230 mesh) in ethyl acetate / dichloromethane (1: 1, v / v) to give the free pure base. The product is dissolved in 50 ml of ether and converted to the monohydrochloride by addition of 50 ml of a saturated solution of hydrogen chloride in ether. The solvent was evaporated in vacuo and the residue was dissolved in a minimum of cold ethanol. Addition of ether begins to form crystals. 0.53 g of product is obtained, m.p. 145-148 ° C. Elemental analysis is shown in Table 1.

Example 11

(±) - N - [2- (4-Morpholinyl) -1- (2-bromophenethoxy)] cyclohexane monohydrochloride (Compound No. 11) (i) The starting transaminocyclohexanol was prepared according to Example 1.

(ii) To a cooled (0 ° C) solution of 3.0 g of (+) - trans [2- (4-morpholinyl)] cyclohexanol (16.2 mmol) and 3.4 mL of triethylamine (24 mmol) in 50 mL of water. A solution of 1.55 mL of methanesulfonyl chloride (20.0 mmol) in 50 mL of dichloromethane was added via syringe. Addition takes place over 5 minutes. The reaction mixture was stirred at 0 ^° C for 1 hour and then at room temperature for 3 hours. The reaction mixture was washed twice with 30 ml of water. The combined aqueous layers were extracted with 50 mL of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 5.9 g of crude mesylate.

(iii) To a solution of 0.60 g of sodium hydride (80% oil dispersion washed three times with 10 ml of hexane, 25 mmol) in 50 ml of dry dimethylformamide was added a solution of 4.00 g of 2-bromophenethyl alcohol (20 mmol) in 50 ml of dry dimethylformamide. . After the addition gas evolved and the reaction mixture was stirred at room temperature for 3 hours. The mesylate prepared in (ii) is dissolved in 50 ml of dry dimethylformamide and the resulting solution is added rapidly (2 min) to the above reaction mixture by syringe. The reaction mixture was heated at 85 ° C for 2 hours and then the temperature was lowered to 45 ° C and stirred overnight. The reaction mixture was poured into ice-water (800 ml) and extracted with ethyl acetate (3.times.200 ml). The combined organic extracts were washed with 300 mL of saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 8.4 g of an oil which was dissolved in 1.0 M aqueous hydrochloric acid. The acidic aqueous solution is extracted three times with 100 ml of ether and the pH is then adjusted to 10 by addition of 50% aqueous sodium hydroxide solution and extracted three times with 100 ml of ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 2.8 g of crude free amino ether. The crude product is purified by chromatography on silica gel 60 (70-230 mesh) in ethyl acetate / dichloromethane (1: 1, v / v) to give the free pure base. The product is dissolved in 50 ml of ether and converted to the monohydrochloride by addition of 50 ml of a saturated solution of hydrogen chloride in ether. The solvent was evaporated in vacuo and the residue was dissolved in a minimum of cold ethanol. The addition of ether begins to form crystals which are separated in two portions. 0.74 g of product is obtained with a melting point of 140-142 ° C. The elemental analysis is shown in Table 1.

Example 12

(±) - trans- [2- (4-Morpholinyl) -1- (3- (3,4-dimethoxyphenyl) -1-propoxy)] cyclohexane monohydrochloride, (Compound No. 12) (i) The starting transaminocyclohexanol is prepared according to of Example 1.

(ii) To a cooled (0 ° C) solution of 3.0 g of (±) -trans- [2- (4-morpholinyl)] cyclohexanol (16.2 mmol) and 3.4 mL of triethylamine (24 mmol) in 50 mL A solution of 1.55 mL of methanesulfonyl chloride (20.0 mmol) in 50 mL of dichloromethane was added via syringe. Addition takes place over 5 minutes. The reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature for 3 hours. The reaction mixture was washed twice with 30 ml of water. The combined aqueous layers were extracted with 50 mL of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give the crude mesylate.

(iii) To a solution of 0.60 g of sodium hydride (80% oil dispersion washed three times with 10 ml of hexane, 27 mmol) in 50 ml of dry dimethylformamide was added a solution of 3.93 g of 3- (3,4-dimethoxyphenyl) -1- of propanol (20 mmol) in 50 mL of dry dimethylformamide. After the addition gas evolved and the reaction mixture was stirred at room temperature for 90 minutes. The mesylate prepared in (ii) is dissolved in 50 ml of dry dimethylformamide and the resulting solution is added rapidly (2 min) to the above reaction mixture by syringe. The reaction mixture was heated to 90 ° C for 90 minutes and then the temperature was lowered to 45 ° C and stirred overnight. The reaction mixture was then poured into 800 ml of ice-water and extracted three times with 200 ml of ethyl acetate. The combined organic extracts were washed with 300 mL of saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 8.5 g of crude product, which was dissolved in 200 ml of 15% aqueous hydrochloric acid and extracted twice with 100 ml of ether. The pH is then adjusted to 10 by addition of 50% aqueous sodium hydroxide solution and extracted twice with 100 ml of ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo. The crude product is chromatographed on silica gel 60 (70-230 mesh) in ethyl acetate / dichloromethane (1: 1, v / v) to give the free pure base. The product is dissolved in 80 ml of ether and converted to the monohydrochloride by addition of 80 ml of a saturated solution of hydrogen chloride in ether. The solid precipitate was collected, dissolved in a minimum amount of warm ethanol, and a large excess of ether was added to begin crystallization of the title compound. Mp 175 177 ° C. Elemental analysis is shown in Table 1.

Example 13

(±) - trans - [2- [Bis (2-methoxy-ethyl) -amino) -1- (2-naphthenethoxy)] -cyclohexane monohydrochloride (Compound No. 13) (i) A mixture of 25 ml of bis- (2-methoxy-ethyl) -amine (169 mmol), 17.2 ml of cyclohexene oxide (170 mmol) and 5 ml of water are heated under reflux for 30 hours. The cooled reaction mixture was partitioned between 200 mL of 10% aqueous sodium hydroxide and 200 mL of diethyl ether. The aqueous layer was extracted twice with 100 mL diethyl ether. The combined organic layers were washed with 8 mL of water and dried over sodium sulfate. The solvent was evaporated in vacuo to give a crude product which was vacuum distilled to give 26.4 g of a clear colorless oil.

(ii) To a cooled (0 ° C) solution of 4.63 g of (+) - trans- [bis (2-methoxy-ethyl) amino] cyclohexanol (16.2 mmol) and 3.4 mL of triethylamine (20.0 mmol) in A solution of 1.55 ml of methanesulfonyl chloride (20.0 mmol) in 50 ml of dichloromethane was added via syringe to 50 ml of dichloromethane. Addition takes place over 5 minutes. The reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature for 4 hours. The reaction mixture was washed twice with 30 ml of water. The combined aqueous layers were extracted with 50 mL of dichloromethane. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 4.87 g of crude mesylate.

(iii) To a solution of 0.60 g of sodium hydride (80% oil dispersion washed three times with 10 ml of hexane, 25 mmol) in 50 ml of dry dimethylformamide was added a solution of 3.4 g of 2-naphthenethanol (20.0 mmol) in 50 ml. of dry dimethylformamide.

Upon addition, hydrogen bubbles are released. The reaction mixture was stirred at room temperature for 90 minutes. The mesylate prepared in (ii) is dissolved in 50 ml of dry dimethylformamide and the resulting solution is added rapidly (over 3 minutes) via syringe to said reaction mixture. The reaction mixture was heated at 90 ° C for 2 hours and then the temperature was lowered to 40 ° C and stirred overnight. The reaction mixture was then poured into 800 ml of ice-water and extracted three times with 200 ml of ethyl acetate. The combined organic extracts were washed with 300 mL of saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent in vacuo gave 8.1 g of an oil which was dissolved in 50 ml of 1M aqueous hydrochloric acid and made up to 200 ml with water. The acidic aqueous solution was extracted twice with 100 mL of ether. The pH is then adjusted to 10 by addition of 50% aqueous sodium hydroxide solution and extracted twice with 100 ml of ether. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 3.58 g of crude amino ether. The crude product is purified by chromatography on silica gel 60 (70-230 mesh) in methanol / dichloromethane (2: 8, v / v) to give the free pure base. The product is dissolved in 50 ml of ether and converted to the monohydrochloride by adding 50 ml of a saturated solution of hydrogen chloride in ether. Evaporate the solvent in vacuo to give 0.75 g of the title compound (without recrystallization).

Example 14

(1R, 2R) / (1S, 2S) -2- (4-Morpholinyl) -1- (3,4-dichlorophenethoxy) cyclohexane monohydrochloride, (Compound No. 14)

The general procedure used to synthesize this compound is analogous to that of Figure 1.

(i) (1R, 2R) / (1S, 2S) -2- (4-Morpholinyl) cyclohexanol:

A mixture of 206.5 ml of cyclohexene oxide (2 mol, 98% purity) and 175 ml of morpholine (2 mol) in 60 ml of water was heated at reflux for 3.5 hours. Then, 5.3 ml of morpholine is added to the reaction mixture and heating is continued for a further 1.5 hours to complete the reaction.

The reaction mixture was then cooled and partitioned between 100 mL of 40% aqueous sodium hydroxide and 200 mL of ether. The aqueous layer was separated and extracted twice with 100 mL of ether. The combined organic extracts were dried over sodium sulfate and the solvent was evaporated in vacuo. Vacuum distillation gave 342.3 g (92.4% yield) of the title compound.

(ii) To a cooled (0 ° C) solution of 40.76 g of (1R, 2R) / (1S, 2S) -2- (4-morpholinyl) cyclohexanol (0.22 mol) and 36.60 ml of triethylamine (0). (26 mol) in 400 ml of dichloromethane is added dropwise a solution of 20.53 ml of methanesulfonyl chloride (0.26 mol) in 50 ml of dichloromethane. The reaction mixture was stirred at 0 ° C for 45 minutes and then at room temperature for 3 hours. It is washed twice with 100 ml of water and the combined aqueous layers are extracted with 100 ml of dichloromethane. The combined organic extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to give the crude mesylate suitable for the next step without further purification.

(iii) 3,4-Dichlorophenethyl alcohol.

To a solution of 7.79 g of lithium aluminum hydride (195 mmol) in 435 mL of anhydrous ether was slowly added (from a solid addition funnel) 27.20 g of solid 3,4-dichlorophenylacetic acid (130 mmol). After addition, the reaction mixture was heated to boiling for 12 hours and then quenched by carefully adding 20 mL of saturated aqueous sodium sulfate solution (20 mL). The resulting solid is filtered off and the filtrate is concentrated in vacuo to give 25.09 g of the desired alcohol.

(iv) To 6.00 g of sodium hydride (0.2 mol, 80% dispersion in oil) in 200 ml of anhydrous ethylene glycol dimethyl ether (200 ml) was added a solution of 38.87 g of 3,4-dichlorophenethyl alcohol (0.2 mol) in 100 ml of anhydrous ethylene glycol dimethyl ether. The resulting mixture was stirred at room temperature under argon for 3 hours.

(v) The mesylate (ii) in 100 ml of anhydrous ethylene glycol dimethyl ether is quickly added to the alkoxide (iv) and the resulting reaction mixture is immediately heated to boiling for 16 hours. 200 ml of water are added to the cooled reaction mixture and the organic solvent is evaporated in vacuo. . The resulting aqueous solution was further diluted with 200 mL of water and the pH adjusted to 1.5 with 10% aqueous hydrochloric acid. The acidic aqueous layer was extracted with 500 mL of diethyl ether to remove unreacted 3,4-dichlorophenethyl alcohol. The pH of the aqueous layer was then adjusted to 5.7 with 5M aqueous sodium hydroxide and then extracted with diethyl ether to give the crude title compound contaminated with some residual mesylate (ii). The organic extract solvent at pH 5.7 is evaporated in vacuo and the residue is then heated to boiling in 200 ml of ethanol / water (1: 1 by volume) by the presence of 4.12 g of sodium hydride (0.1 mol) for 2 hours. hours to hydrolyze the remaining mesylate. The cooled reaction mixture was diluted with 300 mL of water and the organic solvents were evaporated in vacuo. The pH of the remaining aqueous solution was adjusted to 5.7 with 6M aqueous hydrochloric acid and then extracted with 700 ml of ether. The organic extract was concentrated in vacuo to give pure aminoether. The residual product is then partitioned between 300 ml of 1M aqueous hydrochloric acid and 300 ml of dichloromethane. The acidic aqueous solution was then extracted twice more with 300 mL of dichloromethane. The combined organic layers were dried over sodium sulfate, the solvent was evaporated in vacuo and the residue was recrystallized from 700 mL of ethanol-hexane (3: 7, v / v) to give 49.3 g of the title compound. Elemental analysis is shown in Table 1.

Example 15

(1R, 2R) / (1S, 2S) -2- (3-Ketopyrrolidimyl) -1- (1-naphthenethoxy) cyclohexanate monohydrochloride (Compound No. 15)

Synthesis of compound no. 15 corresponds to the reaction sequences of FIGS. 4A and 4B and is described in detail.

(i) N-Benzyloxycarbonyl-3-pyrrolidone:

To a cooled (-60 ° C) solution of 20.0 g of (R) - (+) - 3-pyrrolidinol (98% purity, 224.9 mmol) and 79.2 mL of triethylamine (99% purity, 562 mmol) in 200 ml. A solution of 33.8 mL of benzyl chloroformate (95% purity, 224.9 mmol) in 80 mL of dichloromethane was added dropwise. Addition takes 45 minutes. The reaction mixture (yellow suspension) was allowed to warm to room temperature and stirred overnight under argon. The mixture was then quenched with 350 mL of 1M aqueous hydrochloric acid and the organic layer was separated. The acidic aqueous layer was extracted twice with 150 mL of dichloromethane and the combined organic layers were dried over sodium sulfate. Evaporation of the solvent in vacuo gave 59.62 g of a pale yellow oil which was subjected to high vacuum for 15 minutes to give 58.23 g (yield 17%) of the crude title compound suitable for the next step without further purification.

(ii) N-Benzyloxycarbonyl-3-pyrrolidone.

To a cooled (-60 ° C) solution of 23 mL of oxalyl chloride (98% purity, 258.6 mmol) in 400 mL of dichloromethane was added dropwise a solution of 36.7 mL of anhydrous dimethylsulfoxide (517.3 mmol) in 20 mL of dichloromethane (20 mL). ). The rate of addition is such that the temperature does not exceed -40 ° C. The reaction mixture was then stirred for 15 min. at -60 ° C. A solution of 58.22 g of N-benzyloxycarbonyl-3-pyrrolidinol (step (i), no more than 224.9 mmol) in 80 ml of dichloromethane (80 ml) was then added dropwise. The rate of addition is such that the temperature does not exceed -50 ° C. The mixture was then stirred for 30 min. at -60 ° C and then 158.3 mL of triethylamine (99% purity, 1.125 mol) was added. The resulting mixture was allowed to warm to room temperature and then washed with 600 mL of water, 580 mL of 1M aqueous hydrochloric acid, and 400 mL of water. The organic layer was dried over sodium sulfate and concentrated in vacuo to give 54.5 g of an amber oil which was subjected to 25 min. high vacuum at room temperature. 52.08 g (yield 5.6%) of the crude title compound suitable for the next step are obtained without further purification.

(iii) 7-benzyloxycarbonyl-1,4-dioxa-7-azaspiro [4.4] nonane:

A mixture of 51.98 g of N-Benzyloxycarbonyl-3-pyrrolidinone (step (ii) no more than 224.9 mmol) and 18.8 mL of ethylene glycol (purity 99%, 337.4 mmol) in 180 mL of toluene with 1.04 g p-toluenesulfonic acid monohydrate (5.4 mmol, catalyst) was boiled in a Dean & StaTk for 16 hours. The mixture is then diluted with 250 ml of toluene and washed with 150 ml of saturated sodium bicarbonate solution and twice with 150 ml of saturated sodium chloride solution. The combined aqueous layers were extracted with 100 mL of toluene. The combined organic layers were dried over sodium sulfate and concentrated in vacuo to give 79.6 g of a dark oil. The crude product was dissolved in 500 ml of ethanol and filtered through 80 g of activated carbon to decolorize the solution. The activated carbon is washed with 1000 ml of ethanol and

500 ml toluene. The filtrate was concentrated in vacuo and subjected to high vacuum for 1 hour to give 63.25 g (yield).

6.8%) of the crude title compound suitable for the next step without further purification.

(iv) 1,4-Dioxa-7-azaspiro [4.4] nonane:

A mixture of 34.79 g of 7-benzyloxycarbonyl-1,4-dioxa-7-azaspiro [4.4] nonane (step (iii), no more than 123.7 mmol) and 13.9 g of 10% palladium on carbon at 90 ° C. 1 L of ethanol was hydrogenolyzed in a Parr apparatus at room temperature for 1.5 hours at 60 psi. The catalyst was filtered off, the solvent was evaporated in vacuo and the residue was exposed for 20 min. high vacuum. 15.86 g of the title compound are obtained (yield 99.3%).

(v) (1R, 2R) / (1S, 2S) -2- (1,4-Dioxa-7-azaspiro [4.4] non-7-yl) -cyclohexanol:

A mixture of 23.54 g, 4-dioxa-7-azaspiro [4.4] nonane (step (iv), no more than 182 mmol), 22.6 mL of cyclohexene oxide (98% purity, 219 mmol) and 7.8 mL of water was heated at 80 ° C for 2 hours. The reaction mixture was then partitioned between 60 mL of 40% aqueous sodium hydroxide and 120 mL of diethyl ether. The basic aqueous layer was extracted twice with 120 mL of diethyl ether. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. The residue was subjected to high vacuum stirring at 50 ° C for 1 hour (to remove excess cyclohexene oxide). 32.79 g of the title compound are obtained (yield 79.3%).

(vi) To a cooled (0 ° C) solution of 27.47 g of (1R, 2R) / (1S, 2S) -2- (1,4-dioxa-7-azaspiro [4.4] non-7-yl) of cyclohexanol (120 mmol, step (v)) and 15.86 g of triethylamine (15.86 g) in 240 ml of dichloromethane are added dropwise 18.23 g of methanesulfonyl chloride (156 mmol). The reaction mixture was stirred at 0 ° C for 45 minutes and then at room temperature for 3 hours. The reaction mixture is then washed with 120 ml of a saturated solution of sodium bicarbonate and water (1: 1, v / v). The wash layer was separated and extracted with 120 mL of dichloromethane. The combined organic extracts were dried over sodium sulfate, the solvent was evaporated in vacuo and the residue was subjected to high vacuum for 4 hours. The crude mesylate is obtained suitable for the next step without further purification.

(vii) To 4.32 g of sodium hydride (144 mmol) suspended in 80 ml of anhydrous ethylene glycol dimethyl ether was added a solution of 25.31 g of 1-naphthenethanol (144 mmol) in 80 ml of anhydrous ethylene glycol dimethyl ether. The resulting mixture was then stirred at room temperature for 4 hours.

(viii) (1R, 2R) / (1S, 2S) -2- [1,4-Dioxa-7-azaspiro [4.4] non-7-yl] -1- (1-naphthethoxy) -cyclohexane:

To the alkoxide (vii) is added rapidly a solution of the mesylate (vi) in 80 mL of anhydrous ethylene glycol dimethyl ether, and the resulting mixture is immediately heated to boiling under argon for 66 hours. The cooled reaction mixture was quenched with 200 mL of water and the organic solvent was evaporated in vacuo. The remaining aqueous solution was diluted with 500 mL of water and acidified to pH 0.5 with 10% aqueous hydrochloric acid. The acidic aqueous layer was extracted twice with 500 mL of diethyl ether to remove unreacted 1-naphthenethanol. The pH of the aqueous solution was adjusted to 4.8 with 5 M aqueous sodium hydroxide and then extracted with 600 mL of diethyl ether. The pH of the aqueous solution was further adjusted to 5.7 and extracted with 600 mL of diethyl ether. The same procedure was repeated at pH 6.5 and 12.2. Gas chromatography showed that the organic extracts at pH 4.8, 5.7 and 6.5 contained the title compound, while the ether extract at pH 12.1 contained only unknown impurities. The organic extracts at pH 4.8, 5.7 and 6.5 were combined and dried over sodium sulfate. The solvent was evaporated in vacuo and the residue subjected to high vacuum for 3.5 hours to give 35.82 g (75% yield) of the title compound suitable for the next step without further purification.

(ix) (1R, 2R) / (1S, 2S) -2- (3-ketopyrrolidinyl) -1- (1-naphthethoxy) cyclohexane monohydrochloride:

A solution of 13.73 g of (1R, 2R) / (1S, 2S) 2- [1,4-dioxa-7-azaspiro- [4,4] non-7-yl] -1- (1-naphthenethoxy) -cyclohexane (36 1.0 mmol, step (viii)), 50 ml of 6M aqueous hydrochloric acid and 200 ml of 2-butanone were heated to boiling for 12 hours. The butanone was evaporated in vacuo and the remaining aqueous solution was made up to 250 ml with water. The aqueous solution was extracted twice with 200 ml diethyl ether and then twice with 200 ml dichloromethane. The combined dichloromethane extracts were dried over sodium sulfate and the solvent was evaporated in vacuo. The residual oil was azeotroped with toluene. The resulting solid product was vigorously stirred overnight in 500 mL of diethyl ether with occasional scraping to begin crystallization of the reaction product. The resulting solid was collected and solubilized in 10 mL of dichloromethane. Addition of 400 ml of ether starts recrystallization. The solid was collected and dried under high vacuum for 3 hours to give 9.3 g (76% yield) of the title compound. Elemental analysis is shown in Table 1.

Example 16

(1R, 2R) / (1S, 2S) -2- (1-Acetylpiperazinyl) -1- (2-naphthenethoxy) cyclohexane monohydrochloride, (Compound No. 16)

Merge # 16 is prepared by a procedure similar to that of FIG. 1 with further details of Example 14.

(i) (1R, 2R) / (1S, 2S) -2- (1-Acetylpiperazinyl) -1-cyclohexanol:

A mixture of 5 g of 1-acetylpiperazine (39 mmol) and 3.95 ml of cyclohexene oxide (39 mmol) in 1.2 ml of water is heated at reflux for 16 hours. The reaction mixture was then partitioned between 20 ml of 40% aqueous sodium hydroxide and twice with 20 ml of ether. The combined organic extracts were dried over sodium sulfate and the solvent was evaporated, yielding 7.63 g of the title compound as white crystals (yield 87%).

(ii) To a cooled (0 ° C) solution of 3.65 g of (1R, 2R) / (1S, 2S) -2- (1-acetylpiperazinyl) -1-cyclohexanol (16.2 mmol) and 3.4 mL triethylamine (24 mmol) in 50 mL of dichloromethane was added dropwise a solution of 1.55 mL of methanesulfonyl chloride (20 mmol) in 50 mL of dichloromethane. The reaction mixture was stirred at 0 ° C for 1 hour and then allowed to warm to room temperature. It is then washed twice with 50 ml of water and the combined aqueous layers are extracted with 50 ml of dichloromethane. The combined organic extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to give the crude mesylate suitable for the next step without further purification.

(iii) To a suspension of 0.8 g of sodium hydride (24 mmol, washed twice with 15 ml of hexane) in 50 ml of anhydrous dimethylformamide was added a solution of 2-naphthenethanol in 50 ml of anhydrous dimethylformamide. The resulting mixture was stirred at room temperature for 30 minutes.

(iv) (1R, 2R) / (1S, 2S) -2- (1-Acetylpiperazinyl) -1- (2-naphthenethoxy) cyclohexane monohydrochloride:

To the mixture of alkoxide (iii) was quickly added mesylate (ii) as a solution in 50 mL of anhydrous dimethylformamide and the resulting mixture was heated at 80 ° C for 16 hours. The cooled reaction mixture was poured into 800 ml of ice-water and extracted three times with 200 ml of ethyl acetate. The combined organic extracts were washed with 200 ml of saturated sodium chloride solution and the solvent was evaporated in vacuo. The residual oil is taken up in 80 ml of water and the resulting aqueous solution is acidified to pH 2 with 6M aqueous hydrochloric acid. The acidic aqueous solution is extracted three times with 40 ml of ether to remove unreacted 2-naphthenethanol. The aqueous layer was adjusted to pH 10 with 50% aqueous sodium hydroxide solution and extracted three times with 40 ml diethyl ether. The combined organic extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to give the crude free amino ether, which was chromatographed on silica gel in ethyl acetate-dichloromethane (1: 1, v / v) to give the pure free base. Conversion to the hydrochloride is accomplished with ethereal hydrochloric acid followed by recrystallization from ethanol-diethyl ether to give the title compound. Elemental analysis is shown in Table 1.

Example 17

(1R, 2R) / (1S, 2S) -2- (3-Ketopyrrolidinyl) -1- (2,6-dichlorophenethoxy) cyclohexane monohydrochloride, (Compound No. 17)

Compound No. 17 was prepared by 10 steps according to the procedure of Example 16. Steps (i) and (v) are identical to Example 16.

(vi) To a cooled (0 ° C) solution of 27.77 g of (1R, 2R) / (1S, 2S) -2- (1,4-dioxa-7-azaspiro [4.4] non-7). -yl) -cycloheptanol (120 mmol) and 22 mL of triethylamine (156 mmol) in 240 mL of dichloromethane were added 12.32 mL of methanesulfonyl chloride (156 mmol). The reaction mixture was stirred at 45 min for 45 min. and then 3 hours at room temperature. The reaction mixture was washed twice with 100 ml of water and the combined aqueous layers were washed with 120 ml of dichloromethane. The combined organic extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to give the crude mesylate, which was subjected to high vacuum for 4 weeks before use in step (ix).

(vii) To a suspension of 13.75 g of lithium aluminum hydride (365.75 mmol) in 500 mL of anhydrous diethyl ether was added 50 g 2,6-dichlorophenylacetic acid (243.75 mmol) via a solid addition funnel. The resulting reaction mixture was heated to boiling for 16 hours and then quenched by the slow addition of 25 mL of saturated aqueous sodium sulfate. The resulting slurry was stirred for 3 hours and then filtered. The insoluble material is carefully washed twice with 100 ml of diethyl ether. The combined ether filtrates were dried over sodium sulfate and the solvent was evaporated in vacuo to give 38.6 g (85% yield) of the title compound.

(viii) To 4.32 g of sodium hydride (144 mmol, 90% oil dispersion) in 80 mL of anhydrous ethylene glycol dimethyl ether was added a solution of 27.65 g of 2,6-dichlorophenethyl alcohol (144 mmol) in 80 mL of anhydrous ethylene glycol dimethyl ether. The resulting mixture was stirred at room temperature for 4 hours under argon.

(ix) (1R, 2R) / (1S, 2S) -2- [1,4-Dioxa-7-azaspiro [4.4] non-7-yl] -1- (2,6-dichlorophenethoxy) -cyclohexane:

The mesylate (vi) in 80 ml of anhydrous ethylene glycol dimethyl ether was quickly added to the mixture of the oxide (viii) and the resulting mixture was immediately heated to boiling for 66 hours. The cooled reaction mixture was poured into 200 ml of water and the organic solvent was evaporated in vacuo. The remaining aqueous solution is made up to 700 ml with water, acidified to pH 0.5 with aqueous 6M hydrochloric acid and extracted twice with 600 ml of diethyl ether. The pH of the aqueous layer was adjusted to 5.9 and the aqueous solution was then extracted with 700 mL of diethyl ether. The organic extract was dried over sodium sulfate and the solvent was evaporated in vacuo to give 34.0 g of the title compound (yield 70%).

(x) (1R, 2R) / (1S, 2S) -2- (3-ketopyrrolidinyl) -1- (2,6-dichlorophenethoxy) cyclohexane monohydrochloride:

A mixture of 15.85 g of (1R, 2R) / (1S, 2S) -2- [1,4-dioxa-7-azaspiro [4.4] non-7-yl] -1- (2,6-dichlorophenethoxy) of cyclohexane (38.9 mmol, step (ix)) and 100 ml of aqueous 6M hydrochloric acid in 400 ml of 2-butanone are heated at reflux for 16 hours. The cooled reaction mixture was diluted with 100 mL of water and the organic solvent was evaporated in vacuo. The organic layer was further diluted with 400 mL of water and extracted with 500 mL of dichloromethane and twice with 600 mL of dichloromethane. The combined dichloromethane extracts were dried over sodium sulfate and the solvent was evaporated in vacuo. Azeotropic distillation with toluene gave the title compound which was further dried under high vacuum for 1 min. The hydrochloride is crystallized by overlaying in diethyl ether, the crystals are collected and recrystallized from ethanol-diethyl ether to give 11.85 g of pure product (yield 77%). Elemental analysis is shown in Table 1.

Example 18

(1R, 2R) / (1S, 2S) -2- [1,4-Dioxa-7-azaspiro [4.4] non-7-yl] -1- (1-naphthenethoxy) -cyclohexane monohydrochloride, ( Compound No. 18)

To 1.2 g of (1R, 2R) / (1S, 2S) -2- [1,4-dioxa-7-azaspiro [4.4] non-7-yl] -1- (1-naphthenethoxy) cyclohexane ( 3.14 mmol, Example 15, step (viii)) in 80 mL of diethyl ether was added ethereal hydrogen chloride. The solvent was evaporated in vacuo and the residue taken up in diethyl ether. Overlaying afforded a solid which was collected and precipitated from dichloromethane-diethyl ether to give 0.85 g of the title compound. Elemental analysis is shown in Table 1.

Example 19

(1R, 2R) / (1S, 2S) -2- (Morpholinyl) -1 - [(2-trifluoromethyl) phenethoxy] cyclohexane monohydrochloride, (Compound No. 19) (i) 2- (4-Morpholinyl) cyclohexanone:

To a cooled (-70 ° C) solution of 20 mL of oxalyl chloride (0.23 mol) in 500 mL of dichloromethane was added dropwise a solution of 34 mL of anhydrous dimethylsulfoxide (0.48 mol) in 50 mL of dichloromethane, and the resulting mixture was stirred for 5 min. at a temperature below -60 ° C. Then a solution of 37.05 g of (1R, 2R) / (1S, 2S) -2- (4-morpholinyl) cyclohexanol (0.2 mol) in 50 ml of dichloromethane is added dropwise (the temperature is kept below -60 ° C). and the reaction mixture is stirred for 15 min. 140 ml of triethylamine are then added dropwise while keeping the temperature of the mixture below -50 ° C. The mixture was then allowed to warm to room temperature and then poured into 600 ml of water and the aqueous layer was separated and extracted twice with 500 ml of dichloromethane. The combined organic layers were dried over sodium sulfate and the solvent was removed in vacuo. Vacuum distillation gave 35.1 g (96% yield) of the title compound.

(ii) 2- (4-Morpholinyl) cyclohexanol:

To a cooled (0 ° C) suspension of 2.14 g of sodium borohydride (56 mmol) in 120 mL of isopropanol was added a solution of 24.7 g of 2- (4-morpholinyl) cyclohexanone (135 mmol, step (i)) in 80 mL of isopropanol. The resulting reaction mixture was stirred for 10 min. at 0 ° C and then 30 min. at room temperature. 200 ml of water are then added and the organic solvent is evaporated in vacuo. The remaining aqueous solution was then extracted four times with 50 ml of ethyl acetate. The combined organic extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to give 22.48 g of the title compound suitable for the next step without further purification.

(iii) (1S, 2R) / (1R, 2S) -2- (4-Morpholinyl) cyclohexyl-2- (trifluoromethyl) phenylacetate:

A mixture of 7.41 g of 2- (4-morpholinyl) cyclohexanol (40 mmol, step (ii)), 10.21 g of 2- (trifluoromethyl) phenylacetic acid (49 mmol) and 40 mg of p-toluenesulfonic acid monohydrate in 60 ml of toluene is boiled in a Dean & Stark for 48 hours. To the cooled reaction mixture was added 40 mL of saturated sodium bicarbonate solution, the aqueous layer was separated and extracted three times with 50 mL of ethyl acetate. The combined organic layers were dried over sodium sulfate and the solvent was evaporated in vacuo to give (1S, 2R) / (1R, 2S) -2- (4-morpholinyl) cyclohexyl-2- (trifluoromethyl) phenylacetate and (1R, 2R). ) / (S, 2S) -2- (4-morpholinyl) cyclohexyl-2- (tri-fluoromethyl) phenyl acetate. Dry chromatography of the cis / trans mixture with ethyl acetate-hexane (+ 0.5% isopropylamine, v / v) gave 3.19 g of the crude title compound contaminated with the starting 2- (4-morpholinyl) cyclohexanol. The crude product was partitioned between dichloromethane (30 mL) and 0.5 M aqueous hydrochloric acid (7 mL). The aqueous layer was separated and further extracted twice with 18 mL of dichloromethane. The combined organic layers were dried over sodium sulfate and the solvent was evaporated in vacuo. Recrystallization from ethanol-hexane gave 2.78 g of the title compound.

(iv) (1S, 2R) / (1R, 2S) -2- (4-Morpholinyl) -1 - [(2-trifluoromethyl) phenethoxy] cyclohexane monohydrochloride:

To a mixture of 1.64 g of (1S, 2R) / (1R, 2S) -2- (4-morpholinyl) -cyclohexyl-2- (trifluoromethyl) phenylacetate (4.28 mmol, step (iii)) and 332 mg of sodium borohydride ( A solution of 8.2 ml of boron trifluoride diethyl etherate (65 mmol) was added under boiling over a period of 1.5 hours while stirring in 35 ml of anhydrous tetrahydrofuran. The reaction was quenched by the addition of 70 mL of water, the organic solvent was evaporated in vacuo and the pH of the remaining aqueous solution adjusted to 9.6. The aqueous layer was extracted twice with 70 mL diethyl ether, the combined organic extracts were dried over sodium sulfate and the solvent was evaporated in vacuo. The residue is then partitioned between 50 ml of 0.5 M aqueous hydrochloric acid and twice with 50 ml of diethyl ether. The pH of the aqueous solution was adjusted to 5.9 and the solution was extracted with 50 mL of diethyl ether. The organic layer was separated, dried over sodium sulfate and the solvent was evaporated in vacuo to give the crude free aminoether. The free base was converted to the hydrochloride by partitioning between 10 mL of 0.5 M aqueous hydrochloric acid and 10 mL of dichloromethane. The acidic aqueous solution was extracted with 10 mL of dichloromethane and the combined organic extracts were dried over sodium sulfate and the solvent was evaporated in vacuo. Recrystallization from ethanol-hexane gave 636 mg (38% yield) of the title compound. Elemental analysis is shown in Table 1.

Example 20

(1R, 2R) / (1S, 2S) -2- (3-Ketopyrrolidinyl) -1- [3- (cyclohexyl) propoxy] cyclohexane monohydrochloride, (Compound No. 20) (i) 3-Cyclohexyl-1- propyl bromide;

To a cooled solution (0 ° C) of 5 g of 3-cyclohexyl-1-propanol (35.15 mmol) was slowly added a solution of 1.1 mL of phosphorus tribromide (17.6 mmol) in 2 mL of dichloromethane. After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 4 hours. The reaction mixture was then quenched by the addition of 5 mL of saturated sodium bicarbonate solution and 10 mL of 10% aqueous sodium hydroxide. The resulting mixture was extracted three times with 50 ml of diethyl ether, the combined organic extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to give an oil. Vacuum distillation gave 3.4 g (47% yield) of the title compound.

(ii) (1R, 2R) / (1S, 2S) -2- [1,4-Dioxa-7-azaspiro [4.4] non-7-yl] -1- [3- (cyclohexyl) propoxy ] cyclohexane:

To a suspension of 200 mg of sodium hydride (8.33 mmol) in 20 ml of anhydrous dimethylformamide was added a solution of 1.5 g of (1R, 2R) / (1S, 2S) -2- (1,4-dioxa-7-azaspiro). [4,4] non-7-yl) -cyclohexanol (6.6 mmol) in 10 mL of anhydrous dimethylformamide. The resulting mixture was stirred for 30 min. at room temperature. A solution of 1.67 g of 3- (cyclohexyl) propyl bromide (8.15 mmol) in anhydrous dimethylformamide was then added rapidly. The reaction mixture was stirred at room temperature for 16 hours and then poured into 200 ml of water and extracted three times with 50 ml of ethyl acetate. The combined organic extracts were washed with 50 ml of saturated sodium chloride solution and the solvent was evaporated in vacuo. The residue is taken up in 50 ml of water and the pH is adjusted to 1.0 with aqueous 6M hydrochloric acid. The acidic aqueous solution is extracted twice with 50 ml of diethyl ether and the pH is then adjusted to 5.0-5.5 with 5m aqueous sodium hydroxide and extracted and three times with 50 ml of diethyl ether. The combined organic extracts are concentrated in vacuo at pH 5.0-5.5 to give the crude title compound suitable for the next step without further purification.

(iii) (1R, 2S) / (1S, 2R) -2- (3-ketopyrrolidine) -1- [3- (cyclohexyl) propoxy] cyclohexane monohydrochloride:

(1R, 2R) / (1S, 2S) -2- [1,4-Dioxa-7-azaspiro [4,4'-non-7-yl] -1- [3- (cyclohexyl) propoxy] cyclohexane (ii) solution in 100 ml of a 6M aqueous hydrochloric acid / butanone mixture (1: 4, v / v) was heated to boiling for 16 hours. The cooled reaction mixture was concentrated in vacuo and the remaining aqueous solution was diluted with 50 mL of water. The acidic aqueous solution is extracted with 50 ml of diethyl ether and then three times with 50 ml of dichloromethane. The dichloromethane extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to give the crude title compound. The hydrochloride was crystallized by overlaying in 200 mL of diethyl ether-hexane (1: 1, v / v) and then precipitated from dichloromethane-diethyl ether-hexane to give 0.8 g of the title compound. Elemental analysis is shown in Table 1.

Example 21

(1R, 2R) / (1S, 2S) -2- (3-Acetoxypyrrolidinyl) -1- (1-naphenoxy) cyclohexane monohydrochloride, (Compound No. 21) (i) (1R, 2R) / (1S) hydrochloride 2S) -2- (3-hydroxypyrrolidinyl) -1- (1-naphthenethoxy) cyclohexane:

To a cooled (0 ° C) solution of sodium borohydride in 20 mL isopropanol was added a solution of 1.4 g of (1R, 2R) / (1S, 2S) -2- (3-ketopyrrolidinyl) -1- (1-naphthenethoxy) cyclohexane monohydrochloride ( The mixture was stirred for 15 min at 0 ° C and then for 30 min at room temperature, then quenched by the addition of water and evaporated to dryness and the residue was washed twice with 20 mL of dichloromethane. The dichloromethane layers were dried over sodium sulfate and the solvent was evaporated in vacuo to give the title compound.

(ii) (1R, 2R) / (1S, 2S) -2- (3-Acetoxypyrrolidin-yl) -1- (1-naphthenethoxy) cyclohexane monohydrochloride:

The intermediate alcohol (i) is then heated to boiling in 15 ml of acetic anhydride for 2 hours. Excess acetic anhydride is removed in vacuo, the residue is taken up in 100 ml of water and extracted twice with 30 ml of diethyl ether. The pH of the aqueous solution is adjusted to 8.0 and the solution is extracted three times with 50 ml of diethyl ether. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo. The residual oil was dissolved in a small amount of dichloromethane and a large volume of diethyl ether was added to begin crystallization of 1.0 g (65% yield) of the title compound. Elemental analysis is shown in Table 1.

Example 22

(1R, 2R) / (1S, 2S) -2- (4-Morpholinyl) -1 - [(2,6-dichlorophenyl) methoxy] cycloohexane monohydrochloride, (Compound No. 22)

Compound No. 22 was prepared by Williamson ether synthesis. To a suspension of 337 mg of sodium hydride (80% oil dispersion, 11 mmol) in 20 ml of ethylene glycol dimethyl ether is added a solution of 2 g of (1R, 2R) / (1S, 2S) -2- (4-morpholinyl) -1-cyclohexanol (10, 8 mmol) in 10 ml of ethylene glycol dimethyl ether. The resulting reaction mixture was stirred at room temperature for 3 hours under argon, then a solution of 2,6-dichlorobenzyl bromide in 10 ml of ethylene glycol dimethyl ether was added and the reaction mixture was heated to reflux for 16 hours. The cooled reaction mixture was poured into 40 ml of water and the organic solvent was evaporated in vacuo. The remaining aqueous solution was diluted with 60 mL of water and the pH was adjusted to 0.5 with 6M aqueous hydrochloric acid. The acidic aqueous solution is extracted twice with 40 ml of diethyl ether and then the pH is adjusted to 5.5. Extraction three times with 50 ml of diethyl ether, drying over sodium sulfate and vacuum vacuum gives the pure aminoether. The hydrochloride is precipitated from the free base with ethereal hydrogen chloride. Recrystallization from acetone-methanol-diethyl ether gave 1.6 g (68% yield) of the title compound. Elemental analysis is shown in Table 1.

Example 23

(1R, 2R) / (1S, 2S) -2- (3-Ketopyrrolidinyl) -1- [2,6-dichlorophenyl) methoxy] cyclohxane monohydrochloride, (Compound No. 23)

Compound No. 23 was prepared by 7 steps according to Example 15. Steps (i) to (v) are identical to Example 15. The ether synthesis (step vi) was carried out according to Williamson ether synthesis as in Example 22.

(vi) (1R, 2R) / (1S, 2S) -2- [1,4-Dioxa-7-azaspiro [4.4] non-7-yl] -1 - [(2,6-dichlorophenyl) ) methoxy] cyclohexane:

To a suspension of 22 mg of sodium hydride (80% oil dispersion, 7.25 mmol) in 20 ml of ethylene glycol dimethyl ether was added a solution of 1.5 g of (1R, 2R) / (1S, 2S) -2- (1,4-dioxa-7). -azaspiro [4.4] non-7-yl) cyclohexanol (6.60 mmol, step (v) in Example 15) in 10 mL of ethylene glycol dimethyl ether. The resulting reaction mixture was stirred at room temperature for 2 hours and then a solution of 1.9 g of 2,6-dichlorobenzyl bromide (7.9 mmol) in 10 ml of ethylene glycol dimethyl ether was added. The reaction mixture was heated to boiling under argon for 16 hours, then the solvent was evaporated and the residue was taken up in 70 ml of water. The aqueous solution was acidified to pH 0.5 with 6M aqueous hydrochloric acid and then extracted twice with 40 ml diethyl ether. The pH of the aqueous solution is then adjusted to 4.5-5.5 and the solution is extracted four times with 40 ml of diethyl ether. The combined organic extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to give the title intermediate.

(vii) (1R, 2R) / (IS, 2S) -2- (3-Ketopyrrolidin-yl) -1 - [(2,6-dichlorophenyl) methoxy] cyclohexane monohydrochloride:

The ketal intermediate of step (vi) was heated to boiling in 100 ml of a 6M aqueous hydrochloric acid / butanone mixture (1: 4, v / v) for 16 hours. The butanone was evaporated in vacuo and the remaining aqueous layer was diluted with 100 mL of water. The acidic aqueous layer was extracted twice with 40 ml diethyl ether and then three times with 40 ml dichloromethane. The combined dichloromethane extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to give the crude title compound. The product is crystallized by overlaying in diethyl ether and reprecipitated from dichloromethane-diethyl ether to give

1.8 g (72% yield) of the title compound. Elemental analysis is shown in Table 1.

Example 24

(1R, 2R) / (1S, 2S) -2- (3-Hydroxy-pyrrolidinyl) -1- (2,6-dichlorophenethoxy) -cyclohexane monohydrochloride, (Compound No. 24)

To a solution of 5.0 g of compound no. 17 (12.7 mmol) in 120 mL isopropanol was added 2.0 g of powdered sodium borohydride (52.8 mmol) and the resulting mixture was stirred at room temperature until complete conversion. The reaction mixture is quenched with 40 ml of water and then concentrated to dryness, the residue is washed with 50 ml of dichloromethane, the filtrate is dried over sodium sulphate and concentrated in vacuo. The title compound is crystallized after 3 hours under high vacuum. Elemental analysis is shown in Table 1.

Example 25

(1R, 2R) / (1S, 2S) -2- (3-Ketopyrrolidinyl) -1- (2,2-diphenylethoxy) cyclohexane monohydrochloride, (Compound No. 25)

Compound No. 25 is prepared by 10 steps identical to the steps of Example 15 and 17. Steps (i) to (v) are identical to the steps of Example 15.

(vi) To a cooled (0 ° C) solution of 2.0 g of (1R, 2R) / (1S, 2S) - (1,4-dioxa-7-azaspiro [4.4] non-7-yl) cyclohexanol (8.8 mmol) and 2.1 ml triethylamine (15 mmol) in 30 ml dichloromethane were added 0.9 ml methanesulfonyl chloride (11.44 mmol). The reaction mixture was stirred for 45 min. at 0 ° C and then at room temperature for 3 hours. It is then diluted with 25 ml of dichloromethane, washed twice with 25 ml of water and the combined aqueous layers are extracted with 25 ml of dichloromethane. The combined organic extracts were dried over sodium sulfate and the solvent was evaporated in vacuo to give the crude mesylate, which was subjected to high vacuum for 30 minutes and then used in the next step (ix).

(vii) To a mixture of 2.85 lithium aluminum hydride (23.56 mmol) in 150 mL of anhydrous diethyl ether was added 5.0 g of diphenylacetic acid powder (56 mmol). The resulting reaction mixture was heated to gentle boiling for 1 hour. The mixture was then quenched with saturated aqueous sodium sulfate and the resulting precipitate was filtered off. The filtrate was concentrated in vacuo to give 4/0 g (yield 86%) of the title compound.

(viii) To a mixture of 253 mg of sodium hydride washed with bexane (10.56 mmol) and 15 ml of ethylene glycol dimethyl ether was added a solution of 2.09 g of 2,2-diphenylethyl alcohol (10.56 mmol, step vi i) in 15 ml of ethylene glycol dimethyl ether. The resulting mixture was stirred for 30 min. at room temperature under argon.

(ix) (1R, 2R) / (1S, 2S) -2- (1,4-Dioxa-7-azaspiro [4.4] non-7-yl) -1- (2,2-diphenylethoxy) cyclohexane :

To the alkoxide (viii) is rapidly added the mesylate (vi) in 20 mL of ethylene glycol dimethyl ether. The reaction mixture was heated to reflux for 5 days. It is then cooled, concentrated in vacuo, the residue taken up in 50 ml of water and the pH adjusted. to 1.0 with 6M aqueous hydrochloric acid. The acidic aqueous solution is extracted twice with 50 ml of diethyl ether, the aqueous layer is separated and its pH is adjusted to 6.0 and extracted twice with 50 ml of diethyl ether, dried over sodium sulfate and the solvent is evaporated off under vacuum. Thus, 1.55 g (43% yield) of the title compound are obtained.

(x) (1R, 2R) / (1S, 2S) -2- (3-ketopyrrolidinyl) -1- (2,2-diphenylethoxy) cyclohexane monohydrochloride:

A mixture of 1.55 g of (1R, 2R) / (1S, 2S) -2- (1,4-dioxa-7-azaspiro- [4,4] non-7-yl) -1- (2,2- diphenylethoxy) cyclohexane (3.8 mmol) and 50 mL of a mixture of 6M aqueous hydrochloric acid and butanone (1: 4, v / v) were heated at reflux for 2 hours. The butanone is evaporated in vacuo and the residue is taken up in 50 ml of water. The aqueous solution was extracted twice with 50 ml of diethyl ether, the aqueous layer was separated and extracted twice with 50 ml of dichloromethane. The combined dichloromethane extracts were dried over sodium sulfate and concentrated in vacuo to give the crude title compound. The product was crystallized by overlaying in diethyl ether and precipitating from dichloromethane-diethyl ether to give 1.21 g (80% yield) of the title compound. Elemental analysis is shown in Table 1.

Example 26

(1R, 2R) / (1S, 2S) -2- (3-Thiazolidinyl) -1- (2,6-dichlorophenethoxy) cyclohexane monohydrochloride, (Compound No. 26) (i) (1R, 2R) / ( S, 2 S) -2- (3-Thiazolidinyl) cyclohexanol:

To 12.93 g of anhydrous magnesium perchlorate (53.3 mmol) was added a solution of 6.1 ml of cyclohexene oxide (58.6 mmol) in 25 ml of anhydrous acetonitrile, and the resulting mixture was stirred for 20 min. at room temperature. A solution of 5.16 g of thiazolidine (55.0 mmol) in anhydrous acetonitrile is then added and the reaction mixture is heated at 35 ° C for 16 hours. The reaction mixture is concentrated in vacuo and the residue is partitioned between 350 ml of water and 350 ml of diethyl ether. The aqueous layer was extracted with 350 mL diethyl ether. The combined organic extracts were dried over sodium sulfate and concentrated in vacuo to give the crude product. The crude aminolal alcohol was purified by column chromatography in ethyl acetate-hexane (1-1 volume) to afford 4.83 g (47% yield) of the title compound.

(ii) To a cooled (0 ° C) solution of 3.17 g of (1R, 2R) / (1S, 2S) -2- (3-thiazolidinyl) cyclohexanol (16.9 mmol) and 3.08 ml of triethylamine (22). (0 mmol) in 30 mL of dichloromethane was added dropwise 1.74 mL of methanesulfonyl chloride (22.0 mmol). The reaction mixture was stirred at 0 ° C for 1 hour and then at room temperature for 3 hours. The reaction mixture was diluted with 20 mL of dichloromethane and washed twice with 30 mL of water. The combined aqueous layers were extracted with 25 mL of dichloromethane and the combined organic extracts were dried over sodium sulfate. The solvent was evaporated in vacuo to give the mesylate suitable for the next step without further purification.

(iii) To a mixture of 608 mg of sodium hydride (80% oil dispersion, 20.28 mmol) and 30 ml of ethylene glycol dimethyl ether was added a solution of 3.87 g of 2,6-dichlorophenethyl alcohol (20.28 mmol), Example 4, step (vii). in 15 ml ethylene glycol dimethyl ether. The resulting mixture was stirred at room temperature for 2 hours under argon.

(iv) (1R, 2R) / (1S, 2S) -2- (3-Thiazolidinyl) -1- (2,6-dichlorophenethoxy) cyclohexane monohydrochloride

A mixture of the mesylate (ii) and 15 ml of ethylene glycol dimethyl ether was quickly added to the alkoxide (iii) and the reaction mixture was heated under reflux for 40 hours. The cooled reaction mixture was poured into 100 ml of water and the organic solvent was evaporated in vacuo. The remaining aqueous solution was diluted with 100 mL of water and the pH of the mixture was adjusted to 1.5. The acidic aqueous solution is extracted three times with 100 ml of diethyl ether, the combined organic extracts are dried over sodium sulfate and the solvent is removed in vacuo to give the crude free base. The residue is purified by chromatography on silica gel in ethyl acetate-hexane (1:10, v / v) to give 2.4 g of crude free aminoether. The pure product (1.0 g) was converted to the hydrochloride by treatment with ethereal hydrogen chloride and the resulting salt was recrystallized from acetone-diethyl ether to give 0.69 g of the title compound. Elemental analysis is shown in Table 1.

Example 27

(1R, 2R) / (1S, 2S) -2- (3-Ketopyrrolidinyl) -1- (1-naphthenethoxy) cyclohexane monohydrochloride, (Compound No. 27)

Compound No. 27 is prepared by 8 steps according to the synthesis of FIG. 3. Steps (i) to (iv) are identical to Example 15.

(v) (1R, 2R) / (1S, 2S) -1- (1-Naphthethoxy) -2-cyclohexanol:

To a mixture of 270 mg of anhydrous magnesium perchlorate (1.2 mmol) in 1.7 mL of anhydrous acetonitrile was added 0.12 g of cyclohexene oxide (1.2 mmol). The resulting mixture was stirred for 15 min. at room temperature and then 2.7 g of 1-naphthenethanol (10.15 mmol) are added. The reaction mixture is heated to boiling at a rate of 0.4 ml / h. 2.0 mL of cyclohexene oxide (2.0 g, 20 mmol) was added. The boiling was stopped after 16 hours and the cooled reaction mixture was partitioned between 50 mL diethyl ether and 30 mL saturated sodium bicarbonate solution. The aqueous layer was separated and extracted twice with 40 ml diethyl ether. The combined organic extracts were washed with 15 ml of water, 15 ml of saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent in vacuo afforded the crude title compound suitable for the next step without further purification.

(vi) 1- (1-Naphthethoxy) -2-cyclohexanone:

To a solution of 1.0 g of (1R, 2R) / (1S, 2S) -2- (1-naphthenethoxy) -1-cyclohexanol (step (v)) in 20 ml of dimethylformamide is added in small portions 5.0 g of pyridinium chromate ( 13.2 mmol) and the resulting reaction mixture was stirred at room temperature for 16 hours. The reaction mixture is poured into 100 ml of water and the resulting slurry is extracted three times with 50 ml of diethyl ether. The combined organic extracts were washed with 30 ml of 1M aqueous sodium hydroxide, 30 ml of saturated sodium chloride solution and dried over sodium sulfate. Evaporation of the solvent gave 1.0 g of the crude title compound suitable for the next step.

(vii) (1R, 2S) / (1S, 2R) -2- (1,4-Dioxa-7-azaspiro [4.4] non-7-yl) -1- (1-naphthethoxy) cyclohexane:

To a solution of 5.17 g 1,4-dioxa-7-azaspiro [4.4] nonane (40 mmol) and 1.79 g 1- (1-naphthenethoxy) -2-cyclohexanone (6.58 mmol, step (vi) 77% purity in 10 ml of anhydrous methanol was added 2.7 ml of 5N methanolic hydrogen chloride solution, followed by 397 mg of sodium cyanoborohydride (6 mmol). The reaction mixture was further diluted with 7 mL of anhydrous methanol and stirred at room temperature for 16 hours. The reaction was quenched by the addition of 40 mL of aqueous 6M hydrochloric acid, the organic solvent was evaporated in vacuo. The remaining aqueous solution is made up to 100 ml with water and the pH is adjusted to 0.5 with 6M aqueous hydrochloric acid. The acidic aqueous layer was extracted with 100 mL of diethyl ether; the aqueous layer was separated and the pH was adjusted to 6.7 with 5M aqueous sodium hydroxide. It is then extracted with 100 ml of diethyl ether, dried over sodium sulphate and evaporated in vacuo. The residue was purified by column chromatography in ethyl acetate-hexane (1: 9 to 1: 6, v / v, with 0.5% isopropylamine). 1.28 g of crude (1R, 2S) / (1S, 2R) -2- (1,4-dioxa-7-azaspiro [4.4] non-7-yl) -1- (1-naphthenethoxy) product were obtained. cyclohexane and (1R, 2R) 2 - (1S, 2S) -2- (1,4-dioxa-7-azaspiro [4.4] non-7-yl) -1- (1-naphthenethoxy) cyclohexane. 1R, 2S) / (1S, 2R) -2- (1,4-dioxa-7-azaspiro [4.4] non-7-yl) -1- (1-naphthethoxy) -cyclohexane and (1R, 2R) (1S, 2S) -2- (1,4-dioxa-7-azaspiro [4.4] non-7-yl) -1- (1-naphthenethoxy) cyclohexane was carried out on preparative HPLC (Waters Delta Prep 4000, PrePak column 40 x 100 mm, isopropanol-hexane 2: 98, v / v, + 0.05% diethylamine) to give 590 mg of the title compound.

(viii) (1R, 2S) / (1S, 2R) -2- (3-Ketopyrrolidin-yl) -1-naphthenethoxy] cyclohexane monohydrochloride:

A mixture of 480 mg of (1R, 2S) / (1S, 2R) -2- (1,4-dioxa-7-azaspiro [4.4] non-7-yl) -1- (1-naphthenethoxy) cyclohexane (1). , 23 mmol, step (vii)) and 40 ml of a mixture of 6M aqueous hydrochloric acid and butanone (1: 4, v / v) were heated at reflux for 2 hours. The organic solvent is evaporated in vacuo and the remaining aqueous solution is diluted to 50 ml with water and extracted twice with 50 ml of diethyl ether and then three times with 50 ml of dichloromethane. The combined dichloromethane extracts were dried over sodium sulfate and the solvent was evaporated in vacuo. The residual oil was further dried by azeotropic distillation from toluene. The title compound was crystallized by overlaying in hexane to give 430 mg (93% yield). Elemental analysis is shown in Table 1.

Table 1

21. ¢. formula calculated found CjjH ^ NOjCI C 70.29, H 1.04. N 3,73% C 69.36, H 8.18, N 3.73% «2 CjJHjoNOjCI C 70.29, H 8.04, N 3.73% C 69.71, H 8.06, N 3.56% «3 Ο Η ,, ^ Ο, ΒΓα C 53.41.H6.72.N 3.46% C53.16, H 6.77, N 3.35% CjjHjeNOjCí C 67.42, H 7.72, N 157% C673J, H 7.75, N 3.59% «5 ChHíjNOjBtCí C5I.3i, H 6.47. N 3.33% σ5138, Η6.21.Ν331% * 6 CmHmNO ^ Cl C62.24, H 8.36 .N 3.63% C 61.69, H 64, N 3.63% 47 C ^ .H «NOCI C73.4I. H 8.40.N 3.Í9% C 73.26. H 4.64. N 3.94% H S CEH NO? SCl C 62.89, H 7.39, N 3 67% C 61.94, H 7.42, N 3.70% # 9 CmHmNOjSCI C 62.89, H 7.39. N 3.67% C 62.53, H 7.56, N 3 «10 Η Ο ,, ,, ΝΟ, ΒγΟ C53.4 !, H ¢ .72. N 3.46% C 53.29. H 6.94. N 3.57% * 11 ϋ., Η, .ΝΟ, ΒΚΖΙ C53.4I, H 6.72. N 3.46% C 52.61. H 7.46. N 4.01% «12 Η Ο ,, ,, ΝΟ, α C 63.06, H 8.57, N 3.50% H, 8.41, N 3.45% * 14 ο 'η _λ νοα C 54.77. H 6.M. K 3.55% C 58.80, H 6.85. N 3.51% Η Ο ,, ,, ΝΟ, α C 70.67. H 7.55. N 3.75% C 70.12, H 7.55. N 3.73% Η σ ,, ,, Νίο, σ.Η, ο C 63.63. Hl 23, N 6.1 C «2.93. H 8.56.N & 05% «17 C.jHj.NOjCIj C 55.05, H 6.16, N 3.57% C 54.39. H 6.30. N 3.49%

zi e. formula Calculate & Itano found > 18 C 68.97, H 7.72, N 3.35% C 68.49, H 7.64. N 3.31% Sf9 C 57.94, H 6.91. N 3.56% C 57.75. H 6.91. N 3.56% * 20 c ,, h _m no, ci C 66.35. H 9.96, N 4.07% C 66.22, H 9.02, N 4.12% «21 Ct.HjjNOjCI H 7.72, C68.97, N 3J5% C67.52.H7.W, N3.t7% m C ^ HmNOjCIj. h ₃ o H, 6.57, N 1.51% C 51.03, H δ .57, N 3-36% Ο ,, ΗηΝΟ, Ο, C 53.9). H 5.86 C 53.88. H 5 79. N 3.59% * 24 CuHjjNOjCI ,. Η, Ο C 52.38, H 6.84, N 3.39% C 53.98, H 725, N3.33% CMH ^ NOjCI C 72.07, H 7.56. N 3.50% OJ C 71.87, H 7.57, N3.51% »26 ο Η ,, ,, Νοα, δ C 51.46, H 6.10, N 3.53% C 51.48. H5.86.N3.44% m CtjHjiNOjCI C 70.67, H 7.55, N 3.75% C 70.63. H 7.53 N 3.65%

Example 28

Evaluation of antiarrhythmic efficacy

Antiarrhythmic efficacy was evaluated by examining the effect of the compound on the incidence of cardiac arrhythmias in conscious rats that underwent coronary artery occlusion. In rats weighing 200-300 g, a preparatory surgical procedure was performed and the rats were divided into randomized groups. In any case, the animals were anesthetized with halothane during surgery. A cannula was inserted into the left femoral artery to measure mean arterial pressure and collect blood samples. A cannula for injecting drugs was also inserted into the left femoral vein. The thoracic cavity was opened and a polyethylene occluder was loosely positioned around the left anterior descending coronary artery. The thoracic cavity was then closed. The ECG was recorded by the attached electrodes placed along the anatomical heart axis. All cannulae and lead wires were led out in the central scapular region. According to random and double-blind selection, they were administered approximately 0.5 to 2 hours after surgery for infusion of the vehicle (vehicle) alone or the test compound. After 15 minutes of infusion, the occlusion was retracted to cause coronary artery occlusion. 30 minutes after occlusion, ECG, arrhythmias, blood pressure, heart rate and mortality were monitored. Arrhythmias were recorded as ventricular tachycardia (VT) and ventricular fibrillation (VF) and scored by Curtis, M.J. and Walker, M.J.A. (Cardiovasc. Res., 22, 656, 1988) (see Table 2).

Table 2

Points Description_____________________________________________

0 -49 VPB

50 - 499 VPB> 499 VPB or 1 episode spontaneously reversible VT or VF> 1 VT or VF episode or both (> 60 s duration overall)

VT or VF or both (60 -119 with duration total)

VT or VF or both (> 119 s duration) fatal VF beginning> 15 min. after occlusion of fatal VF, start a task between 4al4min.59spo occlusion of fatal VF starting between 1 and 3 min. 59 sec after occlusion fatal VF beginning <1 minute after occlusion _______________

VPB = ventricular premature contraction - extrasystole

VT = ventricular tachycardia VF = ventricular fibrillation

Rats were excluded from the study when they had no serum potassium in the range prior to occlusion.

2.9-3.9 mM. The occlusion was associated with an increase in the R wave and an elevation of the "S - T" segment and the occluded area (determined by death by Cardiogreen dye perfusion) ranged from 25% to 50% of the total left ventricular weight.

Table 3 describes test results of compounds described as given infusion rate values in mol / kg / min (ED50AA), which reduced the arrhythmia score in treated animals to 50% of the score reported by animals treated with the vehicle in which the test drug was dissolved only.

Table 3

Compound No. ED ₅₀ AA 1 0.8 2 1.0 3 2.1 4 2.0 5 3.0 6 4.0 7 4.0 8 1.0 9 1.0 10 2.0 11 1.0 14 1.5 15 0.43 17 1.1 19 1.4 21 1.4 22 1.8 23 2.1 24 0.6 25 2.5 26 6.5

Example 29

Measurement of ECG parameters

In this example, rats weighing 200-250 g were used. The animals were anesthetized with pentobarbital 60 mg / kg i.p. Blood pressure and drug injection cannulas were inserted into the carotid vein of the jugular vein, respectively. The ECG was recorded by the attached electrodes placed along the anatomical heart axis. All compounds were administered as bolus injections.

Various ECG parameters were measured. Table 4 describes the test results as ED ₂₅ (mol / kg), which is the dose required to produce a 25% increase in the measured parameter (not = unspecified). Prolongation of PR and QRS intervals indicates blockade of the cardiac sodium channel, while prolongation of the Q-T interval shows blockade of the associated cardiac potassium channel, a property of type 1a antiarrhythmic drugs.

Table 4

Compound No. PR QRS QT 1 not not 2.5 2 5.6 8 2.0 3 32 16 3.0 6 not not not 7 1.1 1.5 0.9 14 - 21.5 1.4 15 15.8 7.8 3.4 17 30 26 4.2 21 1.7 2.3 1.6 23 - 17.2 2.7 24 1.4 1.6 1.0 26 2.3 - 10

Example 30

Evaluation of sodium channel blockade

Rats were prepared according to the foregoing procedure. Two silver stimulation electrodes were inserted through the chest wall and implanted in the left ventricle. Rectangular wave stimulation was used to determine the recording threshold, the ventricular fibrillation threshold, and the effective refractory phase (Howard, PG and Walker, MJ A, Proc. West. Pharmacol. Soc., 33, 123-127, 1990). Table 5 contains the ED25 values for these cardiac sodium channel blockade indicators, where ED ₂₅ is the infusion rate in mol / kg / minute of compound necessary to elicit a 25% increase over controls. Prolongation of the refractory period indicates associated potassium channel blockade. The recording current threshold is labeled "It". The ventricular fibrillation threshold current is designated "VFT". The effective refractory period is labeled "ERP".

Table 5

Compound No. lt VFT ERP 1 2.8 1.4 1.5 2 0.9 0.7 1.3 3 5.8 not 4.0 7 0.7 0.2 0.4 14 6.4 - 1.7 15 5 1.2 1.6 17 6 7.3 7.1 23 7.6 6.2 5 24 1.7 1.2 1.1 26 10.5 9 5.4

Example 31

Canine Models of Vaginal AF General Method

Crossbreeds of both genders weighing 15-49 kg were anesthetized with morphine (initially 2 mg / kg im, followed by 0.5 mg / kg i.v. every 2 hours) and chlorosal (120 mg / kg iv, followed by infusion). , 25 mg / kg / hour, St.Georges et al., 1997).

The dogs were mechanically ventilated with room air supplemented with oxygen through an endotracheal tube at a frequency of 20-25 breaths / minute with the respiratory volume determined from the nomogram. Arterial blood gases were measured and maintained in the physiological range (SAO 2> 90%, pH 7.30 - 7.45). Catheters for recording blood pressure and measuring blood gases and both femoral veins for drug delivery and venous blood sampling were inserted into the femoral artery. Catheters were kept clear by heparinized 0.9% saline. Body temperature was maintained at 37 ° C with an electric blanket.

The heart was exposed by midline thoracotomy and a pericardial bed was formed. Three bipolar Teflon ™ coated stainless steel electrodes were inserted into the right atrium and one was inserted into the ear of the left atrium for recording. A programmable stimulator (Digital Cardiovascular Instruments, Berkeley, CA) was used to stimulate the right atrium with 2 ms pulses of twice the diastole. Two bipolar Teflon ™ coated stainless steel electrodes were inserted into the left ventricle, one for recording and the other for stimulation. An on demand ventricular pacemaker (GBM 5880, Medtronics, Minneapolis, MN) was used to stimulate ventricles at a rate of 90 beats per minute when ventricular rate slowed too much (especially during vagal AF). The P23 ID sensor, clcktrophysiological amplifier (Bloom Associates, Flying Hills, PA) and paper recorder (Astromed MT-95000, Toronto, ON, Canada) were used to record ECG leads II and III, atrial and ventricular EGMs, blood pressure and pacing artifacts . The vagal nerves were isolated on the neck, double ligated and separated, and electrodes were inserted into each nerve (see below). In order to block changes in adrenergic activity on the heart, nadolol was administered at an initial dose of 0.5 mg / kg i. v., followed by 0.25 mg / kg i. in. every two hours.

Atrial fibrillation model (AF)

The effect of drugs on ending permanent AF maintained during continuous stimulation of the vagus nerve was evaluated. Unipolar hook electrodes (made of Teflon ™ protected stainless steel, coated whole except distal 1-2 cm) were inserted through a 21 gauge needle into each nerve parallel to its axis. In most experiments, unipolar stimuli (DS-9F model, Grass Instruments, Quincy, MA) were applied to produce 0.1 ms of 10 Hz rectangular wave pulses and a voltage equal to 60% of the voltage required for asystole formation. In some experiments bipolar stimulation was used. The voltages required to produce asystole ranged from 3 to 20 volts. Under controlled conditions, a short burst of fast atrial pulses (10 Hz, four times the diastolic threshold) was delivered to induce AF, which usually persisted for more than 2c minutes. The vagal stimulation tension was adjusted under control conditions and then compared after each treatment to maintain the same bradycardic effect. AF was defined as a fast (> 500 per minute in control conditions) irregular atrial rhythm with varying morphology on the electrogram.

Measurement of electrophysiological variables and vagal response

The diastolic threshold current was determined at a base cycle length of 300 ms by increasing the current in 0.1 mA increments until a stable recording was achieved. For the following protocols, the current was set to twice the diastolic threshold. Atrial and ventricular ERP was measured by the extrastimulus method over a S1S2 interval at a baseline cycle of 300 ms. Premature extrastimulus S2 was delivered after every 15 baseline stimuli. The S1S2 interval was increased in increments of 5 ms until recording occurred, with the longest interval identically failing to elicit a spreading ERP defining response. The diastolic threshold and ERP were measured repeatedly twice and averaged to produce a single value. These values were generally within 5 ms. The interval between the stimulus artifact and the local electrogram peak was measured as a conductive velocity index. AF Cycle Length (AFCL) was measured during vagal AF by counting the number of cycles (number of strikes -1) at a 2 second interval at each of the atrial recording locations. The average of the three AFCL measurements was calculated to obtain the cumulative average AFCL for each experimental condition.

The stimulus voltage-heart rate relationship in the vagal nerve stimulation was determined under control conditions in most experiments. Vags were stimulated as described by various voltages to detect the voltage that caused asystole (defined as a sinus pause longer than 3 seconds). The response to vagal nerve stimulation was confirmed in each experimental condition and the voltage was adjusted to keep the heart rate response constant to the vagal nerve stimulation. In cases where it was not possible to induce asystole, vagal nerve stimulation was adjusted to voltage, which allowed two two-minute episodes of vagal AF to be maintained in control conditions (see below).

Experimental protocols

The experimental groups studied are summarized in Table 5. Each dog received only one drug at the doses indicated in Table 5. The first set of experiments were dose-variation studies followed by a blinded study in which 1 to 3 doses were administered. All drugs were administered i. in. by means of an infusion pump, whereby drug solutions were prepared freshly into plastic containers on the day of the experiment. Vaginal stimulation parameters were defined in control conditions as described and the duration of AP during 20 minutes of vagal nerve stimulation under control conditions was verified. After completion of AF, the diastolic threshold and atrial and ventricular ERP were determined. Then, these variables were evaluated again in the atrium to stimulate the vagus nerve. Electrophysiological testing usually took 15 to 20 minutes. The heart rate response to vagal nerve stimulation was confirmed and the vagal AF / electrophysiological testing protocol was repeated. A blood sample was taken prior to drug administration and vaginal AF established again. Five minutes later, one of the treatments was given at the dosages listed in Table 5. The total dose was infused over 5 minutes, and a blood sample was taken immediately thereafter. No maintenance infusion was given. If AF was completed within 15 minutes, repeated electrophysiological measurements were obtained under control conditions and a blood sample was taken. When AF was not terminated after the first dose (within 15 minutes), a blood sample was collected and vagal pacing was discontinued to allow return to sinus rhythm. Electrophysiological measurements were repeated and the third and final blood sample was taken for the given dose. AF was induced again and the vagal AF / drug infusion / electrophysiological testing protocol was repeated until the drug was terminated with AF.

Statistical analysis

Group data is expressed as mean ± SEM. Statistical analysis was performed for effective doses for AFCL and ERP using the Bonferroini correction t-test for multiple comparisons. The effect of the drug on blood pressure, heart rate, diastolic pressure and ECG intervals was evaluated for the median dose required to end AF. Bilateral tests were used and p < 0.05 was taken to express statistical significance.

Table 6

Experimental groups and doses of drugs Medicine Dose range tested (mol / kg) benefit effective end AF (mol / kg) Average dose required to complete AF (mol / kg) Median dose required to complete AF (mol / 'kg) Flekalnid 1.25 to 10 4-2,5; 1 - 10 4 ± 2 2.5

Each dog was given one drug at the indicated dose range until AF was complete. The number of dogs in which AF was terminated for each dose (number of dogs - dose, in mol / kg) is shown. The mean ± SEM as well as the median dose required to complete AF is shown. Each dog received only one medicine.

A large number of compounds of the present invention were evaluated by this method. The results show that all compounds tested are successful in terminating AF in a canine vagal AF model. The conversion rate is similar to that reported by many other group I and III drugs in this model. The efficacy of flecainide as a control in the present study was comparable to that previously reported. All drugs prolonged AFCL prior to AF termination, an effect generally consistent with the wavelength in the rc-cntry model at AF termination. Test compounds of the present invention did not reduce blood pressure or heart rate at a median dose to terminate vagal AF. The heart rate response to vagal nerve stimulation was similar in all groups and was not affected by any test compound. Vag nerve stimulation of 60% of the voltage required to induce asystole (10 ± 1 V) caused a 1.3 + 0.1 s pause.

Example 32

Canine models of sterile pericarditis

This model was used to characterize the AF and atrial flutter mechanisms (AFL). Waldo and co-workers found that AF depends on re-entry and that the exit point is usually a slowed-down line. This canine model is prepared by dusting an exposed atrium with talc powder, followed by a salvo of atrial pulses within a few days of recovery. AF can be induced two days after surgery, but on the fourth day after surgery, the predominant inducible rhythm is permanent atrial flutter. The possibility of inducing AF on the second day is somewhat variable, so that only 50% of the dogs had sustained AF (generally <60 minutes) for the required 30 minutes. However, a permanent atrial flutter that developed on day 4 could be induced in most of the prepared animals. Atrial flutter is easier to "map" for drug mechanism detection goals. The possibility of inducing AF resolved on the fourth day after surgery, much like AF, which often develops after heart surgery, mimicking the model of sterile pericarditis. In the etiology of AF after surgery, an inflammatory component may be involved that may determine the degree of selection against ischemia or an acid selective drug. Similarly, although coronary artery bypass graft (CABG) bypass surgery is performed to alleviate ventricular ischemia, these patients may also be at risk of mild atrial ischemia due to ischemic heart disease (CAD). While atrial infarction is rare, there is an association between AV stenosis of the nodal artery and the risk of AF following CABG surgery. Surgical rupture of the autonomic innervation of the atria may also play a role in AF after CABG.

techniques

Studies were conducted in a canine model of sterile pericarditis to determine the ability and efficacy of Compound 1 to terminate atrial fibrillation / flutter. Atrial flutter or ftbrillation was induced 2 to 4 days after the formation of sterile pericarditis in adult canine hybrids weighing 19-25 kg. In all cases, atrial fibrillation or flutter lasted longer than 10 minutes. All studies were conducted according to guidelines set out by the Committee on Ethical Treatment of Laboratory Animals (Institutional Animal Line and Use Committee).

Creation of a model of sterile pericarditis with atrial fibrillation / flutter

A canine model of sterile pericarditis was created as described. During the operation, a pair of FEP-coated stainless steel electrodes were sewn except for the electrode tip (O Flexon, Davis and Geck) into the ear of the right atrium, Bachman beam, and back down into the left atrium near the proximal coronary sinus. The electrode gap between each pair was approximately 5 mm. These wire electrodes were routed through the thoracic wall and led out at the back in the interscapular area for further use. At the end of the operation, the dogs were given antibiotics and analgesics and allowed to recover. Postoperative care included administration of antibiotics and analgesics.

All dogs, beginning on the second post-operative day, were tested to induce permanent atrial fibrillation / flutter in conscious and non-sedated dogs to confirm the possibility of induction and stability of atrial fibrillation / flutter and to test drug efficacy. Atrial rhythm indication was performed with electrodes sewn during the initial surgical procedure. On the fourth postoperative day, when a stable atrial flutter was induced, an open chest study was performed.

For ciclc open chest studies, each dog was anesthetized with pentobarbital (30 mg / kg i.v.) and the dogs were mechanically ventilated with 100% oxygen using the Boylle 50 model anesthesia (Harris Lake, Inc.). The body temperature of each dog was maintained within the normal physiological range during the study using an electric cushion. When the dog was anesthetized, but before the chest was opened, radio frequency ablation of His bundle was performed to create complete atrioventricular (AV) blockade using standard electrode catheter techniques. This was done to minimize overlap of atrial and ventricular complexes during subsequent recording of unipolar atrial electrograms after atrial flutter induction. After complete AV blockade was established, the true ventricular rate was maintained by stimulating the ventricles at a rate of 60 to 80 beats per minute using a Medtronic 5375 pulse generator (Medtronic Inc.) delivering stimuli via electrodes sewn into the right ventricle during initial surgery.

Determination of pacing threshold and refractory period during pacing

One of the two previously described methods was used to induce AF / AFL: (1) introducing one or two premature atrial contractions (atrial extrasystoles) following a sequence of 8 stimulated atrial contractions at a cycle length of 400 ms, 300 ms, 200 ms, or 150 ms, or (2) a rapid atrial rhythm for 1 to 10 seconds at a rate of 10 to 50 beats per minute faster than a spontaneous sinus rhythm until atrial flutter was induced or a 1: 1 atrial record loss occurred. Atrial pacing was performed either by electrodes from the ear atrium of the right atrium, or by electrodes embedded in the lower left atrium. All stimulation was performed using stimuli of twice the threshold for each core sequence with a modified Medtronic 5325 Programmable Battery Stimulator with a pulse width of 1.8 ms.

After induction of permanent atrial fibrillation / flutter (lasting longer than 10 minutes), the atrial fibrillation / flutter cycle length was measured and initial mapping and analysis was performed to determine the location of the atrial fibrillation / flutter reentry circuit. Atrial flutter was defined as a fast atrial rhythm (frequency> 240 beats per minute) characterized by a constant beat-to-beat cycle length, polarity, morphology, and amplitude on the recorded bipolar electrograms.

Protocol of drug efficacy testing

Effective refractory periods (ERP) were measured at three sites: right atrial ear (RAA), posterior left atrium (PLA), Bachman beam (BB) at two baseline lengths of 200 and 400 msec.

2. Induction of AF or AFL by pacing. This was tested for one hour. If no arrhythmia was induced, no further study was conducted on that day.

3. If AF was induced, it had to last 10 minutes. Then it was waiting for spontaneous termination or 20 minutes waiting, whichever happened first.

4. AF was then induced again and left 5 minutes before starting the drug infusion.

5. The drug was then infused as a bolus over 5 minutes.

6. When AF was terminated with the first dose, a blood sample was collected and ERP measurements repeated.

7. The medicine was left for five minutes to stop AF. If no termination occurred, a second dose was administered over 5 minutes.

8. After ERP was completed and measured, a second attempt was made to recall AF within ten minutes.

9. If AF was induced again and lasted for 10 minutes, a blood sample was collected and the study was repeated from the above mentioned no. Third

10. If re-induced AF did not occur, the study was terminated.

Example 33

Assessment of pain blockade

The guinea pigs were shaved (back only) and 6 aliquots (50 L) of the compound solution (10 mg / ml) were indicated immediately under the skin to form 6 blisters which were traced with a permanent marker. Pain responses were evaluated as indicated on each blister at regular intervals up to 14 hours after injection and the duration of pain blockade was recorded in three animals for each test solution.

Table 7

compound Block duration (hours) 1 2.5 2 3 3 2.5 11 3 Saline 0

A large number of compounds of the present invention were evaluated by this method. The results showed that in this model all test compounds were successful at the end of atrial fibrillation / flutter. No emerging arrhythmias or cardiovascular adverse events were observed during drug administration.

All publications and patent applications cited in this specification are hereby incorporated by reference to the same extent as if individual applications or patents were incorporated herein.

It will be apparent from the foregoing that although specific embodiments of the invention are described to illustrate the invention, various modifications may be made without departing from the scope of the invention. Thus, the invention is limited only by the scope of the claims.

Claims (49)

Aminocyclohexyl ether compound of formula (XV) or a solvate thereof, or a pharmaceutically acceptable salt thereof: where independently for each occurrence, R 1 and R _2> when taken together with the nitrogen atom to which they are directly attached in formula (XV), form a ring represented by formula (II): <Z ~ R. I — N i (II), * wherein the ring of formula (II) is formed by a nitrogen atom and at the same time by three to nine other ring atoms independently selected from carbon, nitrogen, oxygen and sulfur; wherein any two adjacent ring atoms may be joined by a single or double bond, and any one or more of the other ring carbon atoms may be substituted by one or two substituents selected from hydrogen, hydroxy, C _r C ₃ hydroxyalkyl, oxo, C ₂ - A C ₄ acyl group, a C 1 -C ₃ alkyl group, a C ₂ -C ₄ alkylcarboxy group, a C ₁ -C ₄ alkoxy group, a C ₁ -C ₄ -alkanoyloxy group, or it may be substituted to form a spiro five or six membered heterocyclic ring containing one or two heteroatoms selected from an oxygen atom and a sulfur atom; and any two adjacent additional carbon ring atoms may be fused to the C ₃ -C ₈ carbocyclic ring, and any one or more additional ring nitrogen is substituted with substituents selected from H, C _r -C ₆ alkyl, C ₂ -C ₄ acyl, C ₂ -C ₄ -hydroxyalkyl and C ₃ -C ₈ alkoxyalkyl; or R! and R ₂ , when taken together with the nitrogen atom to which they are directly attached in formula (XV), may then form a bicyclic ring system selected from 3-azabicyclo [3.2.2] nonan-3-yl, 2-azabicyclo [2.2.2] octan-2-yl, 3-azabicyclo [3.1.0] hexan-3-yl, and 3-azabicyclo [3.2.0] heptan-3-yl; A is selected from any of formulas (III), (IV), (V) and (VI): wherein R _7, R _1o, R, and R _L2 is H, R ₈ and R ₉ are independently selected from hydrogen, hydroxy, fluorine, chlorine, bromine, methanesulphonamido, metanoyloxyskupiny, methoxycarbonyl, nitro, sulfamyl groups, thiomethyl, trifluoromethyl, methyl, ethyl, methoxy, ctoxy and N 1 ·, provided that at least one of R ₈ and R _{9 is} not hydrogen; and Z is selected from oxygen and sulfur; including their isolated enantiomeric, diastereomeric and geometric isomers and mixtures thereof. A compound according to claim 1, selected from the group consisting of: (+) - iran- [2- (4-morpholinyl) -1- (2-naphthenethoxy)] cyclohexane; (-) - traíw- [2- (4-morpholinyl) -l- (2-naphthenethoxy)] cyclohexane; (+) - rra7ís- [2- (4-morpholinyl) -l - (- naphthenethoxy)] cyclohexane; (-) - trans' bis- [2- (4-morpholinyl) -l- (l-naflenetoxy)] cyclohexane; (+) - trans - [2- (4-Morpholinyl) -1- (4-bromophenethoxy)] cyclohexane; (-) - trans- [2- (4-Morpholinyl) -1- (4-bromophenethoxy)] cyclohexane; (+) - trans- [2- (4-morpholinyl) -l- (3,4-dimetoxyfenetoxy)] - cyclohexane; (-) - trans-2- (4-morpholinyl) -1- (3,4-dimethoxyphenethoxy)] - cyclohexane; (+) 4 trans - [2- (1-pyrrolidinyl) -1- (1-naphthethoxy)] cyclohexane; (-) - trans- [2- (l-pyrrolidinyl) -l- (l-naphthenethoxy)] cyclohexane; (+) - trans' 5- [2- (4-morpholinyl) -l- (2- (benzo [b] thiophen-3-yl) ethoxy)] cyclohexane; (-) - trans - [2- (4-Morpholinyl) -1- (2- (benzo [b] thiophen-3-yl) ethoxy)] cyclohexane; (+) - trans 5- [2- (4-Morpholinyl) -1- (2- (benzo [b] thiophen-4-yl) ethoxy)] cyclohexane; (-) - tra '5- [2- (4-morpholinyl) -l- (2- (benzo [b] thiophen-4-yl) ethoxy)] cyclohexane; (+) - / rarw- [2- (4-morpholinyl) -l- (3-bromophenethoxy)] cyclohexane; (-) - trans- [2- (4-morpholinyl) -l- (3-bromophenethoxy)] cyklohexánii; (+) - trans- (2- (4-morpholinyl) -1- (2-bromophenethoxy)] cyclohexane; (-) - trans- [2- (4-morpholinyl) -1- (2-bromophenethoxy)] cyclohexane; (R, 2 R) / (S, 2S) -2- (4-morpholinyl) -l- (3,4-dichlorophenethoxy) cyclohexane; (R, 2 R) / (S, 2S) -2- (3-ketopyrrolidinyl) -l- (l-naphthenethoxy) cyclohexane; (1R, 2R) / (1S, 2S) -2- (1-Acetyl-piperazinyl) -1- (2-naphthylethoxy) -cyclohexane; (R, 2 R) / (S, 2S) -2- (3-ketopyrrolidinyl) -l- (2,6-dichlorophenyl-ethoxy) of cyclohexane; (1R, 2R) / (1S, 2S) -2- [1,4-dioxa-7-azaspiro [4.4] non-7-yl] -1- (1-naphthenethoxy) cyclohexane; (1R, 2S) / (1S, 2R) -2- (4-Morpholinyl) -1 - [(2-trifluoromethyl) phenethoxy] cyclohexane; (1R, 2R) / (1S, 2S) -2- (3-acetoxypyrrolidinyl) -1- (1-naphthethoxy) cyclohexane; (1R, 2R) / (1S, 2S) -2- (3-hydroxypyrrolidinyl) -1- (2,6-dichlorophenethoxy) cyclohexane; (1R, 2R) / (1S, 2S) -2- (3-thiazolinyl) -1- (2,6-dichlorophenethoxy) cyclohexane; and (1R, 2S) / (1S, 2R) -2- (3-ketopyrrolidinyl) -1- (1-naphthenethoxy) cyclohexane; and pharmaceutically acceptable salts thereof, including mixtures thereof. A composition comprising a compound according to claim 1 or 2 in combination with a pharmaceutically acceptable carrier, excipient or diluent. Use of a compound according to claim 1 or 2 in the manufacture of a medicament. A compound or composition according to any one of claims 1 to 3 for use in treating or preventing arrhythmia of a warm-blooded animal. A compound or composition according to any one of claims 1 to 3 for use in modulating the ion channel activity of a warm-blooded animal. A compound or composition according to any one of claims 1 to 3 for use in modulating ion channel activity in vitro. The compound of claim 1 or 2 or the composition of claim 3 for use in the treatment or prevention of a central nervous system disease of a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing convulsions of a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing epileptic convulsions of a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing depression, anxiety or schizophrenia of a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing Parkinson's disease in a warm-blooded animal. A compound according to claim 1 or 2 or a composition according to claim 3 for use in the treatment or prevention of a respiratory disease of a warm-blooded animal. A compound according to claim 1 or 2 or a composition according to claim 3 for use in treating or preventing cystic fibrosis of a warm-blooded animal. A compound according to claim 1 or 2 or a composition according to claim 3 for use in treating or preventing asthma of a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing a cough of a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing inflammation of a warm-blooded animal. A compound according to claim 1 or 2 or a composition according to claim 3 for use in the treatment or prevention of arthritis of a warm-blooded animal. A compound according to claim 1 or 2 or a composition according to claim 3 for use in the treatment or prevention of warm-blooded animal allergies. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing gastrointestinal diseases of a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing urine incontinence in a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in the treatment or prevention of irritation syndrome of the colon of a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing cardiovascular diseases in a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing cerebral or cardiac ischemia of a warm-blooded animal. A compound according to claim 1 or 2 or a composition according to claim 3 for use in treating or preventing hypertension of a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing a long-QT syndrome of a warm-blooded animal. A compound according to claim 1 or 2 or a composition according to claim 3 for use in treating or preventing stroke of a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing migraine in a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing ocular diseases of a warm-blooded animal. her). A compound according to claim 1 or 2 or a composition according to claim 3 for use in the treatment or prevention of diabetes mellitus of a warm-blooded animal. A compound according to claim 1 or 2 or a composition according to claim 3 for use in treating or preventing a warm-blooded animal myopathy. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing Becker myotonia in a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing myasthenia gravis of a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing paramyotonium congentia in a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing malignant hyperthermia of a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing hyperkalemic periodic paralysis of a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing Thomsen myotonia in a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing autoimmune diseases of a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing graft rejection in an organ transplant or bone marrow transplant of a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in producing local analgesia or anesthesia of a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing heart failure of a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing hypotension of a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing Alzheimer's disease in a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in treating or preventing dementia of a warm-blooded animal. A compound of claim 1 or 2 or a composition of claim 3 for use in treating or preventing alopecia of a warm-blooded animal. The compound of claim 1 or 2 or the composition of claim 3 for use in increasing the libido of a warm-blooded animal. A compound or composition according to any one of claims 1 to 3 for use in treating or preventing atrial arrhythmias in a warm-blooded animal. A compound or composition according to any one of claims 1 to 3 for use in treating or preventing ventricular arrhythmias in a warm-blooded animal. A compound or composition according to any one of claims 1 to 3 for use in treating or preventing atrial fibrillation of a warm-blooded animal. A compound or composition according to any one of claims 1 to 3 for use in the treatment or prevention of fibrillation of the chambers of a warm-blooded animal.